Biochimica et Biophysica Acta 1755 (2005) 71 – 89
http://www.elsevier.com/locate/bba
Review
Cellular UV damage responses—Functions of tumor suppressor p53
Leena Latonen, Marikki Laiho*
Molecular and Cancer Biology Program and Haartman Institute, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland
Received 30 August 2004; received in revised form 7 April 2005; accepted 21 April 2005
Available online 16 May 2005
Abstract
DNA damage, provoked by ultraviolet (UV) radiation, evokes a cellular damage response composed of activation of stress signaling
and DNA checkpoint functions. These are translated to responses of replicative arrest, damage repair, and apoptosis aimed at cellular
recovery from the damage. p53 tumor suppressor is a central stress response protein, activated by multiple endogenous and environmental
insults, including UV radiation. The significance of p53 in the DNA damage responses has frequently been reviewed in the context of
ionizing radiation or other double strand break (DSB)-inducing agents. Despite partly similar patterns, the molecular events following UV
radiation are, however, distinct from the responses induced by DSBs and are profoundly coupled with transcriptional stress. These are
illustrated, e.g., by the UV damage-specific translocations of Mdm2, promyelocytic leukemia protein, and nucleophosmin and their
interactions with p53. In this review, we discuss UV damage-provoked cellular responses and the functions of p53 in damage recovery
and cell death.
D 2005 Elsevier B.V. All rights reserved.
Keywords: p53 tumor suppressor; UV radiation; DNA damage; Nucleotide excision repair; Cell cycle arrest; Apoptosis
Contents
1.
2.
Ultraviolet radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Cellular damage caused by UV radiation . . . . . . . . . . . . . .
1.2. Cellular defenses against UV radiation-induced damage. . . . . . .
1.2.1. Repair of UV-induced DNA damage . . . . . . . . . . . .
1.2.2. Cellular stress signaling pathways induced by UV radiation
1.2.3. Transcriptional responses to UV radiation . . . . . . . . .
1.3. Role of UV radiation in skin carcinogenesis. . . . . . . . . . . . .
Tumor suppressor p53 . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Structure of p53 . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. p53 family of proteins . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Regulation of p53 . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.1. Mdm2 in regulation of p53 stability and activity . . . . . .
2.3.2. Transcriptional activity of p53 . . . . . . . . . . . . . . .
2.3.3. PML and NPM—mobile regulators of p53 . . . . . . . . .
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Abbreviations: 6-4PP, 6-4 photoproduct; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia-related; CPD, cyclobytane-type pyrimidine dimer;
DSB, double strand break; GGR, global genomic repair; HDAC, histone deacetylase; HAT, histone acetyl transferase; NB, nuclear bodies; NER, nucleotide
excision repair; NPM, nucleophosmin; PML, promyelocytic leukemia; RNAP, RNA polymerase; ROS, reactive oxygen species; TAD, transactivation domain;
TCR, transcription-coupled repair; UV, ultraviolet; Wt, wild type; XP, Xeroderma pigmentosum
* Corresponding author. Tel.: +358 9 1912 5540; fax: +358 9 1912 5554.
E-mail address: [email protected] (M. Laiho).
0304-419X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbcan.2005.04.003
72
L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
2.4.
Multiple functions of p53 in the DNA damage response . . . . . . . . . .
2.4.1. Cell cycle arrest . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2. DNA repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.3. Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.4. Developmental and senescence-associated roles of p53 . . . . . .
2.4.5. Differences between p53 responses following UV and g-irradiation
2.5. UV response of p53 in vitro and in vivo . . . . . . . . . . . . . . . . . .
2.6. Role of p53 in skin tumorigenesis . . . . . . . . . . . . . . . . . . . . .
2.7. p53 and dose-dependent response to UV—arrest or apoptosis? . . . . . . .
3. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Ultraviolet radiation
UV light is electromagnetic radiation emitted from the
sun (or an artificial source), invisible to the human eye. UV
radiation is divided to three areas according to its wavelength: UVA 315 –380 nm, UVB 280 – 315 nm, and UVC
190 – 280 nm (Fig. 1). The energy content of the radiation is
inversely correlated to its wavelength, rendering UVC the
most harmful component of UV light [1]. The ozone layer
absorbs solar UVC and most of UVB, and it is estimated
that 1 –10% of UV radiation on the surface of Earth is UVB
and over 90% UVA. However, the proportion of shorter
wavelengths is increasing due to stratospheric ozone
depletion [2]. UV radiation has many effects on skin,
including inflammation, immunosuppression, and alterations in the extracellular matrix (ECM), in addition to
accelerated skin aging [3,4]. UV radiation also harms the
eyes, especially by promoting age-related ocular diseases
[5]. The most hazardous effect of excess UV light for
humans is, however, increased risk of skin cancers [6,7].
1.1. Cellular damage caused by UV radiation
Cells contain photosensitive molecules, chromophores,
which, upon receiving photons in UV radiation, subsequently lift electrons to a higher energy state. A chromophore may pass its excited energy to another molecule and
cause a chain reaction [1]. As the occurrence and nature of
these events depend on the chemical structure of the
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chromophore, wavelength of radiation, and specific reaction
conditions, the complexity and amount of different biomolecules result in multiple physical events and alterations
in cellular functions (Fig. 1).
The main cellular chromophores for UV radiation are
DNA and reactive oxygen-generating chromophores. Due to
the aromatic ring structures of its bases, DNA absorbs shortwavelength UV very efficiently and is the main chromophore for UVC, but absorbs also a significant amount of
energy from UVB [8,9]. The most apparent types of UV
radiation-induced DNA damage are cyclobutane-type pyrimidine dimers (CPDs) and (6-4)-photoproducts (6-4PPs),
which cross-link adjacent DNA bases [9]. These UVinduced distortions in the DNA helix halt RNA polymerase
(RNAP) elongation along DNA, thus inhibiting gene
expression [10]. In addition, the active repression of
transcription initiation occurs by phosphorylation of RNAPII [11].
UV radiation-induced oxidative events are frequent with
UVB but become more important following UVA [12] (Fig.
1). Oxidative stress is caused by the induction of reactive
oxygen species (ROS), resulting in, e.g., lipid peroxidation
and additional types of DNA damage. Skin cells defend
against oxidative damage via the cooperation of chemical
and enzymatic antioxidants (reviewed recently in [13]).
Longer UV wavelengths can also induce relatively small
amounts of DNA breaks and DNA –protein cross-links. In
addition, UV radiation can harm lipids and proteins, but the
reproducibility of these cellular molecules makes them
Fig. 1. Physical attributes of UV radiation and types of damage. UV light is divided to three wavelength areas (UVA, UVB, and UVC). The damage that UV
radiation inflicts on cellular chromophores depends on its wavelength, which is inversely correlated to its energy content.
L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
biologically less significant targets for the long-term effects
of UV, such as cellular transformation. Large amounts of
UV radiation can, however, induce the degeneration of the
inner and outer cellular membranes and the inhibition of
macromolecular synthesis and thus cause a chaotic state in
cellular metabolism [1].
1.2. Cellular defenses against UV radiation-induced
damage
Both oxidative and DNA damage caused by UV
radiation provoke adaptive cellular responses, which include
repair events, activation of several signaling cascades, and
changes in transcription [8,14]. The repair of UV-induced
DNA lesions is launched immediately after a UV insult. At
the same time, a cellular response, either a replication arrest
or apoptosis, ensues [15,16]. In skin, the cellular events are
coupled with paracrine events and the following photoprotective responses, such as changes in the ECM, initiation
of inflammation, and increased pigmentation (reviewed in
[17,18]).
1.2.1. Repair of UV-induced DNA damage
The helix-distorting DNA adducts induced by UV
radiation, certain chemicals, and oxidative damage are
repaired by nucleotide excision repair (NER) in mammalian
cells [19]. Lower eukaryotes repair UV-induced DNA
lesions also by the photolyase enzyme [20]. NER involves
20 –30 proteins, each with specific functions [21]. Most
proteins in the recognition and incision steps have been
identified and named according to seven complementation
groups of Xeroderma pigmentosum (XP, XPA to XPG), a
photosensitivity disorder resulting from deficient NER [22].
The NER repair complex is assembled stepwise to the
damage lesion and leads to local unwinding around the
injury by the DNA helicase activity of TFIIH transcription
factor. The damaged strand is incised at approximately 15
nucleotides from both sides of the bulge and is removed.
This is followed by synthesis and ligation to seal the DNA
strand through the action of DNA endonucleases, polymerases, and ligases (for a review, see [19]).
There are two mechanistically different subtypes of
NER, transcription-coupled repair (TCR) and global
genomic repair (GGR) [23,24]. TCR occurs rapidly, in a
gene-dependent manner, and only repairs the template
strand of transcriptionally active DNA. GGR, on the other
hand, occurs slower, repairing also the non-template
strand and the non-transcribed areas. Cell survival
depends more on TCR than GGR [25], but, eventually,
genomic integrity is influenced more by GGR [26]. As
GGR is launched by the XPC –hHR23B protein complex,
recognizing a UV-type of DNA damage [27], TCR is
probably triggered by RNAPII complexes halting at the
UV-induced DNA bulges [10]. During TCR, when repair
enzymes are recruited, they must remove the polymerase
to access the lesion. This occurs either by ubiquitination
73
and the following degradation of RNAPII [28], its
phosphorylation and unstable association with DNA
[11], or by some other, still unresolved mechanism [22].
In addition, TCR requires CS-A and CS-B proteins not
needed for GGR, the deficiency of which results in UV
radiation hypersensitivity disorder Cockayne syndrome
[29]. Furthermore, UV damage causes local inhibition of
transcription around the damaged areas in the nucleus
through the deprivation of TFIIH, which is required for
both NER and transcription initiation [30].
1.2.2. Cellular stress signaling pathways induced by UV
radiation
The DNA damage induced by UV radiation triggers
several signaling cascades to provoke a cellular response.
First, the damage is recognized, following a rapid induction
of a cell cycle arrest (reviewed in [31,32]). The primary
DNA damage sensors include the phosphoinositide-3-kinase
(PI-3-kinase)-related proteins ataxia telangiectasia-mutated
(ATM) and ataxia telangiectasia-related (ATR) [31,33],
which have overlapping functions. ATM is essential for
IR-induced and ATR for UV-induced phosphorylation of
several G1/S checkpoint proteins. ATR and ATM have
multiple targets, including Chk1 and Chk2 kinases, which,
in turn, phosphorylate Cdc25A phosphatase [34]. This leads
to the ubiquitination and rapid degradation of Cdc25A,
rendering the respective cell cycle-driving cyclin E/Cdk2
complex inactive through inhibitory threonine/tyrosine
phosphorylations. Thus, a replicative arrest ensues. These
same kinases take part in the phosphorylation of tumor
suppressor p53 (reviewed in [33]). Cyclin D is also
downregulated [35], which results in increased interaction
of the inhibitory protein p21WAF1/CIP1 with the cyclin E/
Cdk2 complex and prolonged cell cycle arrest [31].
Besides DNA damage-mediated signaling, UV radiation
provokes a cellular response also by additional means [15].
This involves the clustering and internalization of several
cell surface growth factor and cytokine receptors in a ligandindependent manner [36], resulting in the activation of
downstream signaling cascades, the major signal transducers being mitogen-activated protein (MAP), kinases JNK
(jun N-terminal kinase), and p38 [37]. An intracellular
increase in ROS activates MAP kinases through the
activation of Raf and MEKK1 [38]. UV radiation induces
also GTP-binding protein family members Ras, Rac, and
Cdc42, which act upstream of MAP kinases Erk, JNK, and
p38 [39]. The induction of MAP kinases depend on the
dose, time, and wavelength of UV radiation, subsequently
regulating cell growth control, survival, chromatin remodeling, and apoptosis (recently reviewed in [37]).
1.2.3. Transcriptional responses to UV radiation
Several transcription factors take part in the UV response,
of which AP-1 (activating protein 1), NFnB (nuclear factor
nB), and p53 are the most recognized and well characterized
ones. AP-1 transcription factor family members induce
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L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
different sets of target genes and responses depending on
the activating stimuli. AP-1 seems to mostly work in an
antiapoptotic fashion in UV-damaged cells [40,41] and to
regulate several ECM proteins (e.g., matrix metalloproteinases and type I procollagen) [38]. NFnB is activated
both by UV radiation-induced DNA damage and plasma
membrane-originated events [42]. DNA damage provokes
NFnB-dependent production of immunoregulatory cytokines involved in contact hypersensitivity, inflammation,
and immune suppression. NFnB is thought to act mainly
in an antiapoptotic manner, but it has both anti- and
proapoptotic properties [43]. The response resulting from
NFnB activation is determined in collaboration with other
stress-responsive pathways, especially that of p53 [14,
42,44].
Recent technical developments utilizing DNA microarrays have allowed large-scale analysis of transcriptomes.
Transcriptional responses to different wavelengths and
doses of UV radiation have been studied in different cell
types of skin, including keratinocytes [45 – 48], melanocytes
[49], and fibroblasts [50,51]. In general, these cell types
have similar transcriptional targets that involve DNA
damage repair, cell cycle arrest, and/or apoptotic machinery.
However, the transcriptional responses of immunomodulatory factors seem overlapping but distinct, indicating that
the cell types have different roles in the UV radiation
response of skin as an organ. Furthermore, UV doses
causing either cell cycle arrest or apoptosis provoke
transcriptionally highly divergent responses [50]. Not
surprisingly, the downregulation of transcription is very
prominent in apoptotic cells. Yet, we found that the UVinduced repression of transcription is also specific, as the
targets downregulated by a low dose of UV radiation are
different from those downregulated by a high apoptotic dose
of UV [50].
1.3. Role of UV radiation in skin carcinogenesis
The damage induced by solar UV radiation contributes
to all skin cancer types, including basal cell carcinoma,
squamous cell carcinoma (SCC), and cutaneous melanoma.
The occurrence of these cancer types shows correlation to
sun exposure; either the total sun exposure in long term or
episodes of sunburn [8]. The importance of NER in
suppressing UV-induced tumorigenesis is highlighted in
the extremely tumor-prone phenotype of XP complementation groups [52]. Deficiency in the DNA repair of a UV
lesion may result in a mutation within the next two rounds
of cell division, since the damaged bases are often
misinterpreted during DNA replication. Conventional
DNA polymerases cannot bypass a UV lesion, but a
specific DNA polymerase (D) can, although only by
inserting an adenine opposite to the lesion [8]. Even
though this activity is controlled by a proofreading
exonuclease [53], mutations frequently occur, leading
almost exclusively to C-to-T transitions [8]. UV radiation
promotes tumorigenesis also by inducing local and systemic immunosuppression [17].
2. Tumor suppressor p53
p53 is a central factor in cellular stress responses. It
governs the adaptive and protective responses following
several types of exo- and endogenous damage, such as DNA
damage, hypoxia, nucleotide imbalance, oxidative stress,
and spindle damage (Fig. 2) [54]. p53 also reacts to
alterations in cell proliferation induced by the activation of
oncogenes or viral transformation. Upon activation, p53 is
considered to determine the fate of the cell based on the
severity of the damage. It can halt cell cycle progression and
direct damage repair. In case of extensive and unrepairable
damage, p53 induces apoptosis [55,56]. p53 elicits its
normal functions mainly by acting as a transcription factor,
and it regulates genes contributing to the cell cycle, DNA
repair, and apoptosis.
As p53 protein is potentially very harmful to cells, it
must be well controlled. Yet, it has to rapidly react to a
variety of stress signals in a complex manner. Thus, it is not
unexpected that p53 is subject to several regulatory events
and can interact with dozens of other proteins [55]. Distinct
activation pathways exist for p53, and they show specificity
for, e.g., stress stimulus, cell type, and cell growth phase.
Some general mechanisms are common for these pathways:
The p53 protein level is constantly balanced between
synthesis and degradation, by the p53 inhibitory factor
Murine/Human double minute 2 (Mdm2/Hdm2). The
intrinsic activity of p53 can also be modulated, as well as
its localization and interactions with other proteins. Altered
p53 posttranslational modifications may influence these
events [57,58]. In sum, these events contribute to the
outcome of a cellular response driven by p53 activation.
p53 acts as an essential tumor suppressor. Over 50% of
human tumors harbor TP53 mutations, which render p53
protein functionally impaired. This makes TP53 the most
commonly mutated gene in human cancers. It is also
Fig. 2. The tumor suppressor p53 is activated by several forms of cellular
stress, which induce either p53-mediated cell cycle arrest or apoptosis.
L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
speculated that the rest of human tumors have dysfunctional
p53, through its disturbed regulation or protein –protein
interactions by modifiers like ASPP [56]. The essential role
of p53 in tumor suppression is evident by TP53 germline
mutations causing a rare hereditary cancer predisposition,
the Li-Fraumeni syndrome, and p53-deficient animal
models with severely enhanced tumorigenesis [59,60].
p53 was found to be stabilized by UV radiation already in
1984 [61]. Since then, it has become apparent that p53 plays
a central role in the cellular responses provoked by UV
radiation, amongst other stress inducers [55,56]. p53 is
essential for the protective UV responses in skin, and loss of
its function promotes UV-induced skin tumorigenesis
[8,62]. p53 response to IR, perhaps the most widely studied
DNA damaging agent (reviewed recently in [63,64]), shares
several aspects with UV-induced p53 response. However,
significant differences between these responses also exist,
due to the different lesions and damage signaling pathways
activated. The damage recognition and damage-initiated
signaling events differ and may activate p53 by different,
although partly analogous, routes.
2.1. Structure of p53
The TP53 gene is located in the short arm of chromosome 17 (17p13) and belongs to a family with three
identified members in mammals to date. p53 is relatively
well conserved in evolution [65,66] (Fig. 3). Human p53 is
composed of 393 amino acids, with a molecular mass of
43.6 kDa. As most transcription factors, p53 has several
distinct, but interdependent, functional domains with specific properties [55] (Fig. 3). The transactivation domain
(TAD; amino acids 1 –42) is located in the amino-terminal
(N-terminal) part of the protein, next to a proline-rich area
(63 – 97). Sequence-specific DNA binding is mediated
through the central core of p53 (102 –292). The carboxyterminal (C-terminal) part of p53 is composed of a flexible
linker region (300 – 318), oligomerization domain (323 –
356), and a basic, regulatory C-terminal domain (CTD;
363 –393) [55].
The tumor-associated mutations of TP53 are most often
point mutations located in the conserved regions of the
protein, resulting in single amino acid substitutions,
disrupting the DNA binding ability of p53 (reviewed in
75
[55,56]). p53 exists predominantly as a tetramer in solution
(dimer of dimers), which is the most effective oligomer
form in terms of DNA binding [67 – 69]. The p53 protein
is posttranslationally modified to several amino acid
residues by phosphorylation, acetylation, sumoylation,
and glycosylation (Fig. 3). Modifications occur either
constitutively or inducibly, e.g., upon an insult, and affect
p53 activity, its interactions with other proteins, and its
localization. The modifications of p53 following genotoxic
insults have been amply reviewed recently in, e.g., Refs.
[57,58,70].
2.2. p53 family of proteins
p53 has two family members, p63 and p73 [71,72]. They
are strikingly well conserved and have an N-terminal TAD,
a DNA binding domain, and an oligomerization domain
[71,72]. p63 and p73 also possess a C-terminal sterile amotif (SAM) domain, involved in protein – protein interactions, and a post-SAM domain, which has an inhibitory
effect on transactivation. Both p63 and p73 are expressed as
several isoforms, including an isoform devoid of the Nterminal TAD (DNp63/DNp73) [72].
Full-length p63 and p73 bind to many p53 sequencespecific DNA binding sites, transactivate certain p53 target
genes, and induce cell cycle arrest or apoptosis [72,73]. p63
and p73 may inhibit the transcriptional activity of p53 by
competing of the same binding sites on DNA, but also cooperate in target gene activation [74]. DNp63 or DNp73
may inhibit p53 in a dominant-negative fashion through
forming heterocomplexes with p53 [72]. Even though
members of the p53 family of proteins are structurally and
functionally related, p63 and p73 have also distinct
functions. Whereas p53 is essential for cellular stress
responses and tumor suppression, p63 and p73 act during
development in a cell type-specific fashion [72,73,75]. p73
can contribute to the regulation of apoptosis, especially
during neuronal development (reviewed recently in [76]).
p63 is constitutively present in the stem cell compartment of
many epithelial tissues, almost entirely as the transcriptionally inactive DN form [72]. It is needed for sustaining a
viable pool of epithelial stem cells in the skin and is
involved especially in the formation of stratified epithelia
(reviewed in [77]).
Fig. 3. Structure and posttranslational modification of the p53 protein. TAD, transactivation domain; Oligo, oligomerization domain; circles, Ser/Thr
phosphorylation sites; hexagons, acetylation sites; octagons, sumoylation site.
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2.3. Regulation of p53
2.3.1. Mdm2 in regulation of p53 stability and activity
p53 is expressed constantly but, in general, has a short
half-life. p53 is degraded by the 26S proteasome in a
process driven by the ubiquitination of p53 to several Cterminal lysine residues [78]. The major E3 ubiquitin ligase
for p53 is Mdm2 [79,80]. Mdm2 ubiquitinates p53 and
itself, leading to the degradation of both proteins [81 – 83].
However, Mdm2 can only monoubiquitinate p53 [84], and it
relies on its ability to bind histone acetyl transferase (HAT)
p300 to mediate p53 degradation [85,86]. This is due to an
intrinsic ubiquitin ligase activity of p300, by which it
performs p53 polyubiquitination [87]. The monoubiquitination of p53 leads to p53 nuclear export, whereas polyubiquitination activates p53 proteasomal degradation [88].
Furthermore, Mdm2 inhibits the transcriptional activity of
p53 by binding to the p53 TAD [89]. Importantly, Mdm2 is
induced by p53, creating an autoregulatory loop. This
creates an oscillatory response following DNA damage, thus
limiting the rate and duration of the response [90]. Recently,
two other E3 ligases for p53 were identified: Pirh2 and
Cop1, which both ubiquitinate p53 and promote p53
degradation independently of Mdm2 [91,92]. Pirh2 is also
a p53 target gene, possibly forming a feedback regulatory
loop similar to Mdm2 [91].
Even though Mdm2 can shuttle p53 from the nucleus to
the cytoplasm [93], nuclear export is unessential for p53
degradation [94 –96], as p53 can be degraded by both
cytoplasmic and nuclear proteasomes [97]. After stress, p53
accumulates by the dissociation of the p53 –Mdm2 interaction, e.g., through other interacting proteins or changes in
posttranslational modifications of p53 and/or Mdm2 (Fig. 4).
Several Mdm2 phosphorylation sites, both in its N-terminal
p53 binding domain and in its central acidic domain, have
been identified which are essential for p53 ubiquitination
(reviewed in [98]). The best characterized Mdm2-interacting
protein capable of inhibiting p53 degradation is ARF
(alternative reading frame; p14ARF in human, p19ARF in
mice), a small basic protein. ARF interacts with Mdm2 Cterminus and has the capacity to sequester Mdm2 to the
nucleoli, abrogating the ability of Mdm2 to promote p53
degradation (reviewed in [99]). ARF responds to abnormal
cell proliferation resulting from oncogenic stimulus and viral
transformation, but is not essential to the DNA damage
response of p53 [99] (Fig. 4). Other Mdm2 interacting
factors affecting p53 stability are HIF-1a (hypoxia inducible
factor 1a) [100], nucleophosmin (NPM), and promyelocytic
leukemia protein (PML) (see below).
A recently cloned Mdm2 homologue, MdmX, inhibits
p53-mediated transactivation [101]. MdmX does not promote the degradation of p53 but can prevent Mdm2 from
Fig. 4. Regulation of the p53 protein by genotoxic and oncogenic signals.
L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
doing so, thus stabilizing both p53 and Mdm2 [102,103].
The significance of MdmX-mediated regulation of p53 in
DNA damage responses is unclear. Levels of MdmX do not
change after DNA damage, but it can be regulated by
translocation from cytoplasm to nucleus [104,105].
2.3.2. Transcriptional activity of p53
The stabilization of p53 is insufficient for p53-dependent
growth arrest and apoptosis, which, at least in part, require
the transcriptional activity of p53. On the other hand, the
stabilization of p53 is not required for its transcriptional
activity [106], indicating that they are at least partly separate
events. This led to a model in which p53 was thought to
exist in a latent state in nonstressed cells and to become
active upon a stress signal [106]. The regulation of p53
transcriptional activity occurs through its ability to bind
DNA and to interact with other proteins to affect the
formation of an active RNAPII complex. This is affected by
p53 posttranslational modifications and its redox regulation
[107 –109]. As a typical transcription factor, p53 interacts
with several transcription modulating proteins. Interaction
with HATs, such as p300/CBP, and histone deacetylases
(HDACs) affects both the chromatin structure and acetylation status of p53. Interactions with basal transcription
factors TBP, TFIIH, and TAFs and other transcription
factors like Sp1 and Oct-1 promote the formation of an
active RNAPII initiation complex [54,55].
2.3.3. PML and NPM—mobile regulators of p53
Although p53 is predominantly nucleoplasmic, it can
also localize to PML nuclear bodies (PML NBs) following
IR [110,111]. The PML NBs appear to serve as centers for
transcription factor assembly and modification and thus
contribute to transcriptional regulation [112]. p53 localization to PML NBs has been linked to its modification by
covalent attachment of SUMO (small ubiquitin-related
modifier; also called sentrin). The consequence of sumoylation has remained unclear. It is suggested to increase the
transcriptional activity of p53 [113,114], but also contrasting
reports exist [115,116]. The interaction of p53 with PML
and the subsequent localization of p53 to the PML bodies
may modify the transcriptional activity of p53 and influence
its ability to induce apoptosis and cellular senescence
(reviewed in [117]). For example, in the UV response, the
HIPK2-mediated enhancement of p53-dependent transcription relies on the presence of PML [118].
Recently, we showed that UV radiation causes a
redistribution of PML NBs and promotes PML – Mdm2
interaction [119]. p53 and PML interact prior to p53– Mdm2
complex formation and may thus provide an early signal for
p53 stabilization [119]. Furthermore, PML colocalizes with
p53 on sites of DNA repair [120]. PML, Mdm2, and p53
form trimeric complexes at least in vitro [119,121]. PML
appears to increase p53 stability by inhibiting p53 ubiquitination by nucleolar sequestration of Mdm2 [122,123], or
through direct interactions [124]. This suggests that upon
77
UV radiation, PML – Mdm2 –p53 complexes are regulated
in a temporal and spatial manner.
p53 can localize also to the nucleoli, and does so
especially after the inhibition of the proteasome [125 – 127].
This may be attributable to the transcription factor function
of p53, as nucleolar p53 colocalizes with ribosomal RNA
transcription sites [125]. Upon UV radiation, nucleophosmin (NPM), a nucleolar protein, is induced by DNA damage
and increases the UV resistance of cells [128 – 131].
Interestingly, we have shown that after UV insult, NPM is
translocated to the nucleoplasm and binds to Mdm2 [132].
This interaction prevents Mdm2 binding to p53 and
stabilizes p53, thus potentiating the p53 response to UV
radiation [132]. Several other nucleolar proteins also translocate from the nucleoli upon a UV insult (Ki-67, nucleolin,
fibrillarin, p120, and Hrad17) [133 – 136], indicating that
nucleolar reorganization is a major event in the UV
response. In fact, it has been suggested that p53 activation
upon UV radiation, amongst other types of stresses, could
be mediated by nucleolar disruption [135].
2.4. Multiple functions of p53 in the DNA damage response
p53 is a very efficient inhibitor of cell growth. Nonstressed cells overexpressing p53 undergo a G1 arrest
[137,138] or apoptosis [139,140]. These can be separate
events, but many aspects of these responses are in common.
It is not clear how the decision is made whether p53 induces
cell cycle arrest or apoptosis. It can be affected by survival
factors and cross-talk with other pathways controlling cell
proliferation and survival, such as the Rb and NFnB
pathways [56,141]. In addition, the levels of p53 may affect
the outcome, as low levels generally activate cell cycle
arrest whereas high p53 doses induce apoptosis [142]. Low
levels of p53 may, in fact, protect the cells from apoptosis
[143], at least partly due to p53-mediated cell cycle arrest
[56].
p53 mainly exerts its functions by acting as a transcription factor. Several hundred genes are regulated, most
of them induced, by p53 [144]. Bioinformatic approaches
have identified thousands of putative p53 target sequences
in the human genome [145,146]. In addition, the consensus
sequence is not strict and may be influenced by other
regulatory factors. This leaves the exact number of p53
target genes to be clarified. p53 can also specifically repress
several promoters, but the mechanism is poorly understood.
Repression mainly occurs without p53 sequence-specific
DNA binding and most likely depends on p53 interactions
with other proteins, such as TBP [147 –149] and HDACs
via corepressor Sin3 [150].
2.4.1. Cell cycle arrest
p53 arrests the cell cycle in G1 and G2 phases. In the
DNA damage response, the most important transcriptional
targets for p53-induced G1 arrest is p21WAF1/CIP1, a potent
inhibitor of several cyclin-dependent kinase (CDK) com-
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plexes [151]. In S phase cells, p21WAF1/CIP1 may act by
binding to PCNA (proliferating cell nuclear antigen) and
blocking the elongation step of DNA replication [152]. It
may also participate in the G2 arrest by inhibiting cyclin Aand cyclin B-CDK complexes [153]. However, it is not
essential for the G2 checkpoint [154]. At least upon IR, p53induced G2 arrest is enforced by 14-3-3j, which sequesters
and inhibits the mitotic Cdc25C phosphatase [155]. Antiproliferative p53 effects can additionally be mediated by the
induction of BTG2 [156] and the repression of Cdk2 [144].
p53 also takes part in the spindle checkpoint by preventing
mitosis when sister chromatids have failed to segregate
properly [157].
2.4.2. DNA repair
p53 participates in DNA repair and recombination by
regulating transcription and by direct interaction with
components of the repair and recombination machineries.
It possesses 3V–5V exonuclease activity and binds to DNA
lesions and single-stranded DNA [158 – 160]. p53 participates in NER, even though it is not essential for it in vitro
[23]. The abrogation of p53 function by mutation [161] or
targeting by viral proteins [162] renders cells defective in
GGR. Other studies argue that p53 contributes also to TCR
[163 –165]. These contradictions may be due to differences
in the UV radiation wavelengths used in these studies, as
p53 was found to contribute to TCR following UVB but not
UVC radiation [166]. p53 is essential for the efficient GGR
of UV-induced CPDs in human fibroblasts, and it regulates
the efficiency of GGR in the repair of both CPDs and 64PPs [23]. NER-deficient cells accumulate p53 following
lower doses of UV than normal cells and have a prolonged
p53 response, which correlates with the amount of
unrepaired CPDs [167]. How exactly p53 takes part in
NER is still unclear. The main transcriptional target of p53
of the NER complex is the repair factor p48 [23]. The first
p53 target identified, Gadd45 (growth arrest- and DNA
damage-inducible 45), is readily induced by UV radiation
and may promote DNA repair by its association with PCNA
[168]. p53 also upregulates XPC upon UV radiation
[169,170] and induces the transcription of a ribonucleotide
reductase gene p53R2, thereby supplying building blocks
for DNA repair after a genotoxic insult [171].
The transactivation of p21WAF1/CIP1 is not required for
p53 to promote GGR, arguing that the induction of cell
cycle arrest is dispensable for the effect [172,173]. However, conflicting reports exist on whether p21WAF1/CIP1 can
affect NER and/or clonogenic survival after UV (see [174]
and references therein). p21WAF1/CIP1 may affect repair via
its interaction with PCNA, a replication factor also
functioning in NER [152]. UV induces the transition of
soluble PCNA to insoluble, chromatin-bound form [175],
which interacts with the DNA polymerase D responsible for
bulge bypass [176]. The degradation of p21WAF1/CIP1 after
low UV doses is essential for optimal DNA repair [177]. On
the other hand, PCNA remains associated longer with
chromatin after UV irradiation in cells harboring mutant
p53 [178] and in p21WAF1/CIP1 / cells [179]. Thus,
p21WAF1/CIP1 may be inhibitory for the initial stages of
NER, yet its induction may be needed to translocate PCNA
from the repair sites.
p53 directly interacts with several TFIIH-associated NER
factors [163]. p53 associates with RPA needed for DNA
replication, homologous recombination, and NER [19]. The
interaction dissociates upon UV radiation to release RPA for
repair and p53 to induce transcription [180]. Recently, p53
was indicated to contribute to UV-induced GGR by
recruiting HAT complexes to the sites of DNA damage,
thus promoting the chromatin relaxation needed for repair
factors to access the DNA lesions [181].
2.4.3. Apoptosis
The ability of p53 to induce apoptosis may be its most
important tumor-suppressive function [182]. p53 induces
several genes that contribute to both death receptor (Fas/
APO1, KILLER/DR5, and PERP) and mitochondrial (e.g.,
Apaf-1, Bax, Noxa, p53AIP1, and PUMA) apoptotic
pathways [183]. Of these, PUMA and Noxa are absolutely
required for the p53-mediated apoptosis, as demonstrated by
severe impairment of their apoptotic responses in knockdown mice models [184 – 186]. In addition, p53 promotes
apoptosis by activating genes which suppress survival
signaling (e.g., IGF-BP3 (insulin-like growth factor-binding
protein 3)) and by repressing the expression of survivalpromoting or antiapoptotic genes (e.g., IGF-receptor 1, Bcl2, and survivin) [183,187]. The ability to engage various
apoptotic routes has been considered important for the
tumor-suppression function of p53.
p53 apoptotic functions take place both in transcriptiondependent and -independent manners [188,189]. p53 contributes to the shuttling of death receptors to the cell surface
[190] and activates caspase-8 [191]. Mitochondria and
redox regulation appear to be involved in p53 transcription-independent apoptosis. Upon, e.g., ionizing radiationinduced apoptosis, a fraction of p53 is localized in the
mitochondria [192 –195]. There, p53 can directly induce the
permeabilization of the outer mitochondrial membrane by
forming complexes with the antiapoptotic Bcl-XL and Bcl-2
proteins and the proapoptotic Bak, resulting in cytochrome
c release [192 –195]. Whether the mitochondrial translocation of p53 occurs upon UV radiation is currently
unknown.
There are dozens of proteins which may modulate p53mediated apoptosis (for review see, e.g., [56]), but
conclusive evidence for their role in the UV response is
often lacking. p33ING1b enhances UV-induced, p53-mediated apoptosis [196]. ING1 is a tumor suppressor which
inhibits cell growth and induces apoptosis in the presence of
p53 [197]. The expression of ING1 is induced after UV
radiation [198], and p33ING1b, a splice variant of ING1,
can interact with p53 directly and increase the level and
activity of the p53 protein, most likely by competing of
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binding with Mdm2 [197,199]. p33ING1b can also promote
the acetylation and activity of p53 [200] and activate the
transcriptional activities of p63a and p73a [201].
The activities of NER-associated DNA helicases XPD
and XPB are inhibited by the interaction of p53 C-terminus,
which promotes apoptosis (reviewed in [202]). ASPP
proteins specifically stimulate the apoptotic function of
p53, e.g., upon UV, by enhancing the DNA binding and
transactivation function of p53 on the promoters of
proapoptotic genes [203]. ASPP1 and ASPP2 also stimulate
the transactivation function of p63 and p73 on the promoters
of Bax, PIG3, and PUMA, but not Mdm2 or p21WAF1/CIP1
[204]. The WT1 (Wilms tumor 1) protein can interact with
p53, stabilizing it, and inhibit p53-mediated apoptosis
triggered by UV irradiation [205]. WT1 can antagonize
apoptosis also by activating the endogenous Bcl-2 gene
[206] and by inducing p21WAF1/CIP1 independently of p53
[207]. The physiological relevance of these interactions
needs to be determined.
2.4.4. Developmental and senescence-associated roles of
p53
p53 is not essential for the normal development of mice
in utero [208]. During embryogenesis, the transcriptional
activity of p53 is present mainly in the developing nervous
system [209]. After embryonal DNA damage by IR, p53 can
induce apoptotic and antiproliferative responses in vivo cell
type—specifically and mainly in rapidly proliferating
tissues [210 –212]. p53 regulates limited cell proliferation
potential and cellular senescence, which can be seen as
another safeguard mechanism to suppress tumorigenesis
[213,214]. In late passage cultured cells, p53 helps to
maintain a nonproliferative state; a function which is at least
partly due to the ability of p53 to upregulate p21WAF1/CIP1.
The limited replicative potential of human cells is coupled to
shortening of telomeres on chromosome ends during each
round of DNA replication. It is not clear how telomere ends
below a critical length are recognized by the cells, but they
have been suggested to serve as a DNA damage-like signal
inducing p53-mediated damage response [213]. hTERT
(human telomerase reverse transcriptase), the catalytic
subunit of human telomerase, can prevent the shortening
of telomeres by synthesizing telomere DNA and thus
contribute to the increased replicative potential of cells
[213]. p53 downregulates telomerase activity by repressing
hTERT expression [215] and, possibly, via interacting with
hTEP1 (human telomerase-associated protein 1) [216]. It is
noteworthy that fibroblasts expressing hTERT are more
resistant to UV-induced apoptosis [217].
2.4.5. Differences between p53 responses following UV and
c-irradiation
Despite that p53 action is provoked in many similar ways
in response to varying types of damage, like UV and gradiation, certain gross as well subtle differences exist. Key
initiators of the damage response, the damage on the DNA
79
molecule itself, sensors reacting to the lesions, as well as the
repair pathways provoked are clearly distinct [218 – 220].
While IR causes DSBs, the activation of ATM protein
kinase cascade, and the formation of damage induced foci,
UV damage causes transcriptional stress, primarily the
activation of ATR, and activation of NER. So where do
the pathways related to p53 function dissect, and are the p53
and cellular responses really similar? First, p53 is modified
by both ATM/ATR and their downstream kinases Chk1/
Chk2 [33,64]. Though these phosphorylations modify
primarily the p53 aminoterminus within the transactivation
domain, they appear not to be essential for p53 stability nor
transcriptional activity. They may however, provide a more
subtle level of regulation in terms of interaction of p53 with
other molecules or cofactors [57,58,63,64]. Such damagespecific interactions could be reflected by p53 binding to
Brca1 and Rad51 participating in DSB damage sensing
[221 – 223], or by p53 binding to RPA and proteins
participating in NER [224,225]. Interestingly, p73 is also a
target of the Chk2 kinase-E2F1-mediated activation following IR [226]. Whether p73 is also activated by UV radiation
is not known. Secondly, p53 has much faster stabilization
kinetics following IR as compared to UV. While high levels
of stabilized p53 can be detected already within 1 h
following IR, it usually takes 3 h for p53 to accumulate
following UV (see, e.g., [227,228]). This may either reflect
differences in the DNA lesions (DSBs vs. helix distorting
lesions), creating distinct upstream damage sensor signals
initiated at different speeds, or differences in the key events
which initiate p53 stabilization by the loss of its interaction
with its negative regulators, Mdm2, Cop1, or Pirh2.
Similarly, the p53 modification pattern is distinctive,
depending on the type of damage. While IR induces rapid
and transient phosphorylation and acetylation of p53, UV
radiation-induced modifications occur with slower kinetics,
but are more robust in nature [227]. The persistence of the
modifications following UV radiation could reflect sustained damage signaling due to, e.g., slower repair. Few of
the p53 modifications are, however, damage-type specific,
with the notable exception of Ser392 phosphorylation
following UV radiation alone (see [57,58] and references
therein). Lastly, p53 appears to transactivate partly different
sets of target genes depending on the nature of DNA
damage [144]. Few studies have, however, rigorously
compared and assessed the differences in p53 upstream
and downstream events following these very different types
of DNA stress. Such studies should reveal differences in,
e.g., p53 protein – protein interactions affecting either its
stability or activity, or differences in the specificity or
magnitude of p53 target genes regulated, thus dictating
different cellular outcomes.
2.5. UV response of p53 in vitro and in vivo
The effects of UV radiation in the skin are complex due
to its different cell types and layered structure. The lack of
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suitable human material for in vivo studies has not allowed
complex molecular studies. Valuable data has been achieved
using hairless mice, but most of our knowledge of p53
response to UV radiation relies on results from in vitro
models. Comparisons of results from cell cultures and UVdamaged skin have proven cell cultures relevant in studies
of UV-induced cytotoxicity [229]. Sunlight is mostly
restrained to the epidermis, which consists in majority of
keratinocytes. Yet, 10 – 15% of UVB from sunlight penetrates to the dermis, where fibroblasts are located [17].
In normal epidermis, wt p53 is barely detectable (e.g.,
[230,231]). When skin is exposed to sun, p53 accumulates
in the epidermis (basal and immediate suprabasal layers)
and dermis (fibroblasts) [230]. p53 is central to UV
radiation-induced cell cycle arrest and sunburn apoptosis
in skin (e.g., [62,230]), and the inactivation of p53 is
frequent in skin malignancies. It participates in the tanning
response via its potential target genes tyrosinase and TRP-1,
factors required for melanin synthesis [232].
Skin cells respond to UV radiation depending on their
differentiation state and age. Resistance to apoptosis in
growth-arrested keratinocytes is associated with the functional inactivation of p53 [233,234]. Similarly, undifferentiated keratinocytes are relatively resistant to apoptosis
following UV radiation, and the death is independent of
p53. Differentiated keratinocytes, however, exhibit reduced
DNA repair and prevalent p53-dependent apoptosis [235].
The ability of p53 to respond to UV radiation may increase
during keratinocyte differentiation due to several mechanisms. The intrinsic activity of the protein may be enhanced
by C-terminal phosphorylation [236]. DNp63, which is
expressed in the basal layer of the epidermis to maintain the
replicative potential of the epithelial stem cells [72], may
exhibit a dominant-negative effect on p53, which is released
upon differentiation [237]. Interestingly, the expression of
Mdm2 increases as keratinocytes differentiate [231], which
may indicate the transition between ‘‘passive’’ p53 to
actively regulated, UV-responsive p53. In aged cells, the
UV response is impaired. This is due to several factors, e.g.,
lower expression of several DNA damage-responsive
factors, such as ERCC3, PCNA, RPA, and XPA, reduced
ability to accumulate p53, and increased resistance to
apoptosis upon UV radiation (e.g., [238,239]).
2.6. Role of p53 in skin tumorigenesis
p53 is important in skin tumor suppression [8]. As
sunburn is associated with apoptosis, the loss of p53
provides a survival advantage to UV-damaged cells.
Furthermore, lesions with mutant p53 are readily found in
UV-exposed, hairless mouse skin [240] and sun-exposed,
healthy human skin [241]. The activation of p53 can be
observed in chronically sun-exposed skin [242]. TP53 is
mutated in 50% of skin cancers and up to 90% of squamous
cell carcinoma [16]. In addition, TP53 mutations can be
found in up to 90% of tumors in DNA repair-deficient XP
patients [243]. TP53 mutations in non-melanoma skin
cancers often show a ‘‘UV pattern’’, i.e., they are mostly
C-to-T transitions likely to have originated from UV
radiation-induced DNA lesions [16].
Although TP53 mutations are rare in melanomas, the
protein is often stabilized (e.g., [244 – 250]). However, p53 is
often inactive, and the UV responses of human melanoma cell
lines show independency from the p53 function [251]. This
suggests that p53 functions may be suppressed by means
other than mutation, such as the inactivation of the apoptotic
target Apaf-1 [252]. Similarly, ING1 is overexpressed, but
infrequently mutated, in melanoma cell lines compared to
normal melanocytes [198]. Several other p53-related factors
also contribute to skin malignancies. DNp63 levels are
increased in some SCCs [253], suggesting a possible role
for the inhibition of transcription by p63 in this particular
tumor type. Gadd45a / mice are more prone to tumors
upon UV radiation than their wt counterparts, an event that is
linked to inadequate p53 activation [254].
2.7. p53 and dose-dependent response to UV—arrest or
apoptosis?
Cellular response to UV radiation depends on the cell
type, the wavelength, and the dose of UV radiation inflicted
on the cells. Several in vitro studies have used UVC
radiation. Although it is not a physiological wavelength, it
serves as a good model to study the UV-induced bulky DNA
lesions. UVB requires 100-fold more energy to evoke the
same amount DNA adducts [9]. Accounting for this
difference, p53 accumulation, target gene activation, and
cellular responses are similar with UVB and UVC [255].
Even though some influence of oxidative stress cannot be
ruled out, this indicates that p53 stabilization by UVB is
mostly attributable to the DNA lesions.
Low doses of UV radiation induce a transient cell cycle
arrest with the transient induction of p53, whereas high
doses of UV radiation induce apoptosis correlating with a
slower, but more sustained and, perhaps, more pronounced
induction of p53 (e.g., [255 – 258]). In a cell that undergoes
a transient arrest, p53 targets p21WAF1/CIP1 and Gadd45 are
prominently induced, representing the arrest and ongoing
DNA repair, followed by a subsequent induction of Mdm2
terminating the response [257]. The apoptotic p53 UV
response involves the upregulation of apoptotic targets like
Bax and Noxa, the downregulation of anti-apoptotic targets
like Bcl-2, and less or no induction of repair factors or
Mdm2 [50,186,255].
Modifications of p53 occur dose-dependently after UV
radiation [227,255], and especially phosphorylations on
Ser46 and Ser392 have been linked to p53-induced
apoptosis and the UV response [58]. p53 Ser46 is
phosphorylated by HIPK2 (homeodomain-interacting protein kinase-2) after UV radiation, which promotes UVinduced apoptosis [118,259]. This is mediated, at least in
part, by a p53-induced Ser46 phosphorylation-dependent
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increase of apoptosis-promoting p53AIP1 [260]. In addition, the HIPK2-mediated phosphorylation of p53 on Ser46
facilitates CBP-mediated acetylation of p53, resulting in
growth arrest and enhanced UV-induced apoptosis [261].
Phosphorylation on Ser392 may mediate the p53 UV
response by selectively regulating p53-mediated transrepression [262], or by increasing p53 interaction with
nuclear matrix [263]. The significance of other p53
modifications in the UV response is unclear at present.
The regulation of the p53 – Mdm2 pathway is significantly different in cells undergoing a transient arrest and
apoptosis provoked by UV radiation [255]. The transient
arrest response shows a classical feedback loop behaviour of
p53 –Mdm2 regulation, while the apoptotic cells lack the
accumulation of Mdm2 in response to p53 stabilization, and
subsequently, the p53 levels increase further [255,264].
Interestingly, the loss of Mdm2 is sufficient to induce p53dependent apoptosis in vivo [265]. Furthermore, the
susceptibility of UV-induced apoptosis in TCR-deficient
fibroblasts is linked to the lack of Mdm2 induction [266].
Thus, it would seem plausible that apoptosis upon UV
radiation is induced in cells which accumulate p53 to very
high levels and have a repressed Mdm2 induction. This
model is supported by the notion that p53 has, on average, a
lower affinity to binding sites on apoptosis-related targets
compared to targets that induce cell cycle arrest [56].
However, despite the facts that TCR-deficient fibroblasts
show an enhanced accumulation of p53 with lower doses of
UV radiation, lack induction of Mdm2, and are more sensitive
to UV than normal cells are [167,266,267], they do not rely
on p53 for their apoptotic response, as do TCR-proficient
cells [268]. In fact, p53 can protect TCR-proficient cells from
UV-induced apoptosis [161,268,269]. This is substantiated
by in vivo studies showing that Dmp53 is required to protect
Drosophila retinal cells from UV-mediated cell death,
possibly by increasing the rate of damage repair [270].
81
Several factors may contribute to the p53 activities in
response to damage, like the p53-mediated activation of
NER-associated genes or the induction of a replicative arrest
which protects from apoptosis. p21WAF1/CIP1 protects against
p53-mediated apoptosis in human melanoma cells [271] and
in fibroblasts [272]. However, conflicting reports exist on
whether p21WAF1/CIP1 can affect clonogenic survival after UV
(see [174] and references therein), and other cell cycle arrest
and survival factors are likely to be involved.
When is UV-induced apoptosis launched, then? If TCR is
successful, there is still GGR and genomic stability to
accomplish, the failure of which may drive cells to
apoptosis. However, GGR-deficient XPC / mice do not
show enhanced apoptosis upon UV radiation [273]. It may
be that insufficient repair –whether caused by inefficient
TCR or GGR, or just too much damage– drives a cell to
apoptosis. In fact, persistent lesions on DNA halting RNAP
have been suggested to be the signal for p53 induction upon
UV radiation [25,135,267]. The bulky lesions may also be a
key in the selection of p53 target genes, which are activated
dose-dependently. As McKay and coworkers [51] recently
showed, the number of p53-induced genes upon UV
radiation decreases upon an increase in UV dose, resulting
in a shift of spectrum of the induced genes towards those
with smaller size (i.e., more compact genes with smaller and
fewer introns). These correlate with genes which favour
apoptosis [51]. This indicates that persistent transcription
blockage on genes able to rescue cells from UV-induced
damage would be a determinant to UV-induced apoptosis
(Fig. 5).
So far, very little is known about how the UV-induced,
p53-mediated cell cycle arrest is relieved, and whether the
failure of these mechanisms will direct the cells to
apoptosis. At least, the induction of c-jun seems to be
required for the exit from p53-imposed growth arrest, as
cells lacking c-jun have a prolonged cell cycle arrest upon
Fig. 5. p53 UV response. When cells are exposed to UV radiation, p53 accumulates due to the stalling of transcription machinery and/or nucleolar disruption.
p53 activity is influenced by modifications, localization, and protein – protein interactions and leads to increased transcription of genes, commencing cell
cycle arrest. If the transcription block persists, p53 levels are increased further and apoptosis is induced, involving also the transcription-independent activities
of p53.
82
L. Latonen, M. Laiho / Biochimica et Biophysica Acta 1755 (2005) 71 – 89
UV radiation and resist apoptosis [274]. This is due to the
inhibitory effect of c-jun on the promoter of p21WAF1/CIP1,
as cells with a constitutive expression of c-jun do not
upregulate p21WAF1/CIP1 and undergo apoptosis upon UV
radiation [274].
deceptively simple process of p53 stabilization and activation following a specific, but biologically complex, type of
damage induced by UV radiation.
Acknowledgements
3. Concluding remarks
Current evidence supports a dual phase model in the p53
UV response (Fig. 5). UV damage causes immediate stalling
of the transcriptional apparatus due to DNA helix distortions
and sequential assembly of NER complex proteins to the
site of damage. These include XPC-HR23B, followed by
TFIIH and DNA helicases XPB and XPD [27,275]. TFIIH
shifts from being a diffusible transcription factor to the NER
complex and accumulates rapidly (within 2 min) to the site
of damage [276]. The average time of a single NER event (4
min) [277] correlates with the residence time of TFIIH at the
lesion [276]. Though there is no direct evidence that p53
localizes to the lesions, it is required for global chromatin
relaxation, apparently through histone modification and
interactions with several NER components [163,181]. The
imminent DNA damage responses include also a nucleolar
reorganization, which includes translocations of TFIIH,
NPM, and several other nucleolar components from the
nucleoli [132,135,276]. These, especially that of NPM,
participate in the early p53 stabilization response.
Following UV damage, p53 levels and activity are
subsequently increased and lead to transcriptional activation
of its target genes responsible for cell cycle arrest, like
p21WAF1/CIP1. The multiple protein –protein interactions and
modifications of p53, like phosphorylation and sumoylation,
are additional denominators for the p53 action. PML,
translocating to nucleoplasm and to the sites of DNA repair
after UV insult [119,120], interacts with p53 and Mdm2 and
provides a centre for sumoylation events. Combined with
the interactions of NPM with Mdm2 and p53 [132], they
raise the question of how PML and NPM interplay in the
regulation of p53 and Mdm2 and how these link to DNA
repair. The apoptotic p33ING, interacting with and activating p53, is translocated to nucleoli late in the UV response
[278] and may the enhance repair of UV-damaged DNA in a
p53-dependent manner [279]. Studies on the spatial and
temporal interactions of these key factors will shed light
how p53 is regulated in the cellular UV response.
A persistent transcriptional block in the presence of
irrepairable damage launches an apoptotic response. This is
coupled with the inability of the cells to degrade p53, due to
an inadequate increase in Mdm2 levels. It remains to be
determined whether there is specificity for switching off the
activation of Mdm2 by p53 or whether the lack of its
increase reflects general transcriptional shutdown. However,
the apoptotic response combines both transactivationdependent and -independent activities of p53. The data
collectively reveals a high level of diversity in the
Original work in the authors laboratory has been
supported by the Academy of Finland (grant no.
44885), University of Helsinki, Biocentrum Helsinki,
and the Finnish Cancer Organization.
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