COMMENTARY
Mechanisms of the ultraviolet light response in mammalian cells*
SABINE MAI, BERND STEIN, SUSANNE VAN DEN BERG, BERND KAINA,
CHRISTINE LtlCKE-HUHLE, HELMUT PONTA, HANS J. RAHMSDORF, MARCUS KRAEMER,
STEPHAN GEBEL and PETER HERRLICH
Keniforschungszentnim Karlsruhe, Institute of Genetics and Toxicology, PO Box 3640, D-7500 Karlsruhe 1, FRG
*This article is based on a keynote address by Peter Herrlich to the Joint UKEMS and DNA Repair Network Meeting in Brighton, April 1989.
Introduction
Environmental stresses produce physical and/or chemical damage in cells. Commonly, we accept that an
affected cell may either die or repair the damage. Over
the past few years a much more elaborate type of response
to environmental stress has been elucidated. A common
feature of the new type of response is the synthesis of new
macromolecules and the subsequent change in behavior
that could at least in part be defined as 'response
modification'. Transiently, the cells maintain memory of
the particular stress factor and will react differently upon
a second encounter with the same or a related factor.
Examples are the synthesis of heat-shock proteins and the
concomittantly acquired heat resistance (Johnston and
Kucey, 1988; Riabowohl et al. 1988); reduced metal
toxicity by cadmium-induced metal binding proteins
(Beach and Palmiter, 1981; Karin et al. 1983; for earlier
evidence, see Kagi and Nordberg, 1979) and the 'u.v.
response' (Schorpp et al. 1984; Kaina et al. 1989a,fe).
We use the term 'u.v. response' for the genetic changes
that follow irradiation with ultraviolet light (u.v.) or
treatment with other DNA damaging agents (Schorpp et
al. 1984; Kaina et al. 19896). The u.v. response overlaps
with other responses such as those to phorbol esters, to
growth factors and to heat shock. Our laboratory has been
concentrating on two immediate reactions that occur in
u.v.-irradiated human or rodent cells in culture: gene
amplification and induction of gene expression. Several
other laboratories share this interest (Scher and Friend,
1978; Lavi, 1981; Miskin and Ben-Ishai, 1981; Nomura
and Oishi, 1983; Schimke, 1984; Johnson et al. 1986;
Ronai et al. 1987; Valerie et al. 1988; Kartasova and van
de Putte, 1988; Fornace et al. 1988; Yalkinoglu et al.
1988; Karin and Herrlich, 1989; Lambert et al. 1989;
Angulo et al. 1989).
Gene amplification is detected several hours after
treatment of cells either with u.v., gamma or alpha
irradiation, or with one of several DNA-damaging chemical agents. Many portions of the genome can presumably
be amplified. In the absence of selection for the amplified
gene, the amplification is often too low for experimental
Journal of Cell Science 94, 609-615 (1989)
Printed in Great Britain © The Company of Biologists Limited 1989
detection. A simian virus 40 (SV40) T antigen-responsive
origin of replication represents a unique exception.
Although the primary events at origins may well be
identical, T antigen magnifies the response so that a 20fold increase, or more, in copy number is readily seen
(Lavi, 1981). Over-replication occurs several hundred
kilobases in both directions from an integrated SV40
origin (Lticke-Huhle and Herrlich, 1987).
Induction by u.v. irradiation of expression is detected
for many genes (Miskin and Ben-Ishai, 1981; Rahmsdorf
etal. 1982, 1983; Maltzman and Czyzyk, 1984; Schorpp
et al. 1984; Kartasova and van de Putte, 1988; Fornace et
al. 1988) including those coding for the human collagenase and the human immunodeficiency virus (HIV-1)
(Angel et al. 1986, 1987; Herrlich, 1987; Stein et al.
1989a,b). These genes are activated within minutes of
u.v. treatment and gene expression continues for several
hours. By nuclear run-on experiments, the maximal
transcriptional rate of at least some genes is reached
within about 15 min after treatment of the cells.
For didactic reasons we distinguish three consecutive
steps in the u.v. response (Fig. 1), which help in the
discussion of the mechanisms involved. (1) The primary
interaction between the DNA damaging agent relevant to
the response and the cell; (2) signal transduction and
molecular targets; and (3) long-lasting consequences.
The primary interaction
For induced gene amplification it has long been recognized that the replicon examined does not need to absorb
radiation energy or to react with an inducing chemical.
For instance, amplification can be elicited in a nonirradiated, non-treated nucleus upon fusion of the cell
with an irradiated or chemically treated cell (Nomura and
Oishi, 1984; van der Lubbe et al. 1986; Lambert et al.
1986; Liicke-Huhle and Herrlich, 1987). The amplification depended on the dose to which the irradiated cell
was exposed. Thus the site of energy absorption or
primary interaction with the chemical agent could be
distinguished from the site of gene amplification. Pre609
sumably, genes that respond to u.v. by elevated expression (without being amplified) are also entities distinct from the primary target of u.v. absorption. Since
u.v. irradiation of cells leads to the secretion of a factor,
which also activates most of the genes that are activated
by direct u.v. (see below), cell fusion experiments cannot
prove this hypothesis. But dose-target size calculations
lead to a similar conclusion for both induced gene
amplification and gene activation: the genes expressed or
amplified do not need to react directly with the inducing
agent.
u.v. and reactive chemicals can of course alter a large
number of macromolecules in a cell. The relevant target
with respect to the genetic response turned out to be
DNA. One type of evidence stems from a comparison of
induction in cells from either a normal individual or a
patient with Xeroderma pigmentosum. The induction of
gene expression in skin fibroblasts from a patient with
Xeroderma pigmentosum (group A) required a much
smaller dose of u.v. than that required to obtain the same
effect in fibroblasts from a normal individual (Miskin and
Ben-Ishai, 1981; Schorppefa/. 1984; Stein etal. 1989a).
The cells from these two sources are supposed to be
isogenic except for the ability to handle u.v.-induced
photoproducts in the DNA. Cells from a patient with
Xeroderma pigmentosum group A cannot remove photo-
products. At a given time after u.v. treatment, normal
cells will only retain the same number of photoproducts
as the Xeroderma cells, after receiving a much larger dose
(e.g. 10-fold). Thus, one of the photoproducts that
Xeroderma cells cannot remove must be an intermediate
in the activation of genes.
Because of the need for DNA damage, u.v. of wavelength 260nm is most efficient in eliciting the u.v.
response. For instance, the action spectrum for gene
activation in human fibroblasts and in various cell lines
falls steeply to non-detectable effect-levels at wavelengths
longer than 310nm (Stein et al. 1989a). The action
spectrum matches that of pathological changes in human
skin (Longstreth, 1988).
Another very promising approach towards exploring
the primary target of u.v. absorption and carcinogen
action involves the introduction of defined molecules into
cells (we are grateful to Dr Raymond Devoret for
suggesting this approach). We replace the direct treatment of cells by offering cells carcinogen-treated free
DNA. The damaged DNA is introduced either by
transfection or simply by uptake from solution (LiickeHuhle et al. 1989). Structurally altered DNA can indeed
elicit the u.v. response with respect to the two end points
chosen: gene amplification and gene induction (a full
account of these experiments will be published elsewhere
A. Genetic response to genotoxic agents
Immediate
response
Primary action
Photoproducts,
adducts,
radicals,
ionic fluxes
Long-lasting
consequences
Chromosomal
aberrations,
rearrangements,
point mutations
Virus induction,
gene
amplification,
altered program
of
gene expression
Relevant target?
Signal-receiving
structures?
Effector
gene products?
Box 2
Transcription
and replication
factors are
activated:
'early domain'
binding factor,
NF*rB, AP-1,
p67/p62
Box 3
Avoidance of
death and of
mutations by
repair
B. Mechanisms involved
Boxl
u.v. response is
elicited by
DNA damage.
Critical lesions,
e.g. O-6-alkyl-G,
photoproducts
unrepaired
inXPA
i i
Signal transfer
can occur
via the cytoplasm
610
S. Mai et al.
i
Oncogene-driven
mutagenesis
SV40 amplification,
induction of genes
that code for:
transcription factors,
enzymes acting
at the extracellular matrix,
repair and mutator functions
Fig. 1. Operational scheme of the u.v.
response.
soon). The DNA sequence used is irrelevant and does not
need to carry a eukaryotic origin of replication. Thus the
altered DNA is not replicated. So far, u.v., gamma
irradiation and alkylation by A'-methyl-JV'-nitrosoguanidine have been tested with success. In addition,
single-strandedness of DNA may also elicit a response,
although weakly. The alkylated DNA was most effective
in HeLa cells defective in alkylation repair and the effect
was counteracted by supplying the same cells with the
bacterial ada gene (under SV40 promoter control). The
ada gene codes for O-6-G-alkyltransferase (Karran et al.
1979), thus defining O-6-alkyl-G in DNA as one of the
relevant DNA alterations.
We postulate that the altered DNA structure is recognized by a nuclear protein that then elicits a signal that is
transferred to and received by the responding genetic
structures: genes to be amplified or expressed. It is
possible that the nucleus possesses a number of such
proteins recognizing very specific lesions, e.g. O-6-alkylG or thymidine dinners or 6-4 pyrimidine crosslinks. If
this were the case, the signal transductions elicited would
need to merge prior to reaching the responding genes,
since the same genes are stimulated by these treatments
and many lesions cause amplification of genes.
Signal transduction and molecular targets
The site of primary interaction of a carcinogen with the
cell can thus be separated in molecular terms from the site
of the genetic response (box 2 in Fig. 1). Obviously there
must be communication (signal transfer) between these
two separate sites. We will first consider what happens in
box 2 of Fig. 1, and then how the site of DNA damage
communicates with the genetic structures responding: in
our case SV40 DNA and cellular genes. These genetic
structures respond by replication and transcription, respectively. What distinguishes these genes from others
that do not respond, and how is the signal received? In
our laboratory we have discovered that replication and
transcription factors are activated in a post-translational
manner following u.v. irradiation of cells (Stein et al.
1989a; Lucke-Huhle et al. 1989) and that these activations are the limiting steps of the DNA damageinduced genetic changes.
For amplification we assumed that the decisive steps
induced by u.v. would most probably concern the
initiation of replication, and we speculated that u.v.
might increase the activity of a protein binding to the
origin of replication. The SV40 origin in fact binds
several cellular proteins, some of which are more active or
more abundant in u.v.-treated cells. One of those proteins augmented by u.v. is also enhanced by treatment
with alkylating agents (Lucke-Huhle et al. 1989) or alpha
irradiation (unpublished) of cells and binds to the 'early
domain' of the 'minimal origin' of SV40. The increase in
binding occurs in the presence of cycloheximide or
anisomycin. Thus a pre-existing protein is activated by
post-translational modification. Full activation is seen
within 30min. Binding of a protein in the 'early domain'
has been reported (Traut and Fanning, 1988) and the
'early domain' sequence is required for SV40 replication
(Li et al. 1986). If this protein were indeed decisive for
the u.v.-induced amplification process, competing excess
amounts of the early domain DNA sequence introduced
into cells should prevent u.v.-induced amplification.
Indeed, the early domain sequence totally and specifically obliterates the replicative response. From the kinetics of the uptake and the brief half-life of the oligonucleotide we conclude that the early domain protein acts
very early, within the first 2-3 h after the u.v. irradiation.
Thus u.v. treatment leads to the activation of a cellular
replication function acting at the SV40 origin. Another
laboratory has also attempted to identify cellular proteins
involved in viral replication (Ronai and Weinstein, 1988).
Because of the differences in detection methodology a
comparison of the replication proteins must await further
progress.
The transcription of genes is regulated by transcription
factors that bind to specific m-acting regions in the gene
and promote the initiation of transcription by RNA
polymerase (Banerji et al. 1981; Benoist and Chambon,
1981; Dynan and Tjian, 1985; Schlokat and Gruss, 1986;
Ptashne, 1988). These regions are usually assembled in
the 5' flanking region of the gene. Previous work,
particularly with hormone-responsive genes, has shown
that inducible genes are selected for a response on the
basis of specific 'hormone-responsive' sequences
(Chandler et al. 1983; Hynes et al. 1983; Majors and
Varmus, 1983; Karine^a/. 1984). The hormone activates
the specific transcription factor recognizing these sequences (Geisse et al. 1982; Scheidereit et al. 1983;
Payvareia/. 1983). u.v. responsive genes have since been
examined by mutational analysis and specific 'u.v. responsive' cw-acting elements have been found (Stein et
al. 1988; Buschere^/. 1988; Steine/a/. 1989a,6). There
is not just one class of u.v.-responsive elements, but
many. Each of the different elements is supposed to bind
a different transcription factor. Thus there must be
several transcription factors, all of which receive the u.v.induced signals. For the HIV-1 promoter, N F K B seems
to be the relevant transcription factor. Using the KB motif
of the HIV-1 promoter in gel-retardation experiments, a
threefold increase in NF/cB activity is detected in nuclear
extracts within 30min. The activation of NFicB is posttranslational, in a similar or identical manner to that
detected after phorbol ester treatment of cells (Baeuerle
and Baltimore, 1988a,6). Point mutations in the KB motif
prevent both NFfcB binding and u.v. responsiveness of
the HIV-1 promoter. Thus u.v. causes the post-translational activation of NF/cB. Similar arguments can be
given for other genes. Fig. 1 lists two other transcription
factors that respond to u.v. in the absence of new protein
synthesis: AP-1, which is a heterodimer of the proteins
Fos and Jun, and the factors binding to the dyad
symmetry element of c-fos. Thus u.v. activates several
different pre-existing transcription factors.
Knowing some of the signal-receiving structures, replication and transcription factors, we can examine the
communication between the site of primary DNA
damage and these factors. Within 5—10 min a measurable
increase in transcriptional rate of several u.v.-responsive
The u.v. response in mammalian cells
611
genes (HIV-1, collagenase) occurs. NF/cB and 'early
domain' protein activation by the less-sensitive gel shift
technique are well detected at 30 min. The signal transfer
from the origin of the stimulus to these proteins is thus
fairly rapid and operates with and through preformed
macromolecular components, since no new protein synthesis is required (Steinet al. 1989a; Stein, unpublished;
Liicke-Huhle et al. 1989). The location of DNA damage
and the location of the active transcription factors are in
the nucleus. One could imagine a short-cut communication between two nuclear sites. The activation of
NFrfS, however, tells us that signal transduction can pass
through the cytoplasm. Inactive NF/cB is stored in the
cytoplasm where it needs to be released from its stoichiometrically acting inhibitor IKB (Baeuerle and Baltimore,
19886). The release requires a cytoplasmic event.
Whether u.v.-induced signal transduction always passes
the cytoplasm cannot be answered at this time. The
possibility exists that the signal transfer is even more
elaborate, u.v. DNA damage may trigger the release of a
pre-existing growth factor, which then acts on the same
cells and induces a receptor-mediated signal that then
passes through the cytoplasm to the nucleus. There is
some evidence for such a loop involving a released
extracellular factor (Schorpp et al. 1984; Rotem et al.
1987; Stein et al. 19896).
Signal transduction makes use of protein kinases. u.v.induced activation of HIV-1 or collagenase transcription
is blocked by inhibition of protein kinases (Stein et al.
1988). These protein kinases have not been identified and
it is not clear whether they shuttle between cytoplasm and
nucleus, or whether they activate the transcription factors
by phosphorylation or by activating a protein phosphatase or some other modifying enzyme. The nature of the
induced post-translational modification of the transcription factors has resisted unravelling. One of the factors
activated by u.v., AP-1, is phosphorylated (Fos: Curran
et al. 1984; Miiller et al. 1987; Lee et al. 1988; Jun:
Angel et al. 1988) and glycosylated (Jackson and Tjian,
1988). For the 'early domain' protein no such data exist.
Only site-directed mutagenesis affecting the modified
amino acids of the genes coding for these proteins will
help to reveal the relevant modification. Indirect evidence suggests that the types of modification induced by
u.v. and by phorbol esters are similar but not identical.
For instance, the complex and phorbol ester-responsive
SV40 enhancer that has not yet been mentioned here can
be subdivided into single domains (Zenke et al. 1986;
Fromental et al. 1988). Many of these act as enhancers.
We found conditions where the single domains are
equally u.v.- and phorbol ester-inducible, while the
composite enhancer is only u.v.-induced (experiments in
collaboration with P. Chambon). This suggests that the
individual DNA binding protein components are modified to active forms but in their collaboration the type or
site of modification matters.
The conversion of an immediate response to a
sustained response
The communication between the site of DNA damage
612
S. Mai et al.
and the site of action of both transcription and replication
factors is a matter of seconds to minutes. The genetic
response in the nucleus will be turned on instantaneously.
In order to be able to respond again, the cell must
extinguish the 'signal' thereafter. In fact, several levels of
down-modulation have been described for other inducible systems (e.g. see Nishizuka, 1986). These or similar
mechanisms of down-modulation may also apply for the
u.v. response, e.g. inactivation of the enzyme modifying
a replication or transcription factor, or loss of the
modification. Cells have, however, adopted ways of
expanding the response. For the components of the AP-1
transcription factor acting on the collagenase promoter
we know that u.v. increases their synthesis. The
increased level of AP-1 prolongs the secondary response,
e.g. the transcription of collagenase. At 30-60 min after
stimulation the induced transcription of AP-1 is turned
off. This is an autoregulatory process (Schonthal et al.
1988a, 1989; Sassone-Corsi et al. 1988; Konig et al.
1989).
Under abnormal conditions it is conceivable that the
transcription factors remain in the activated form. We
assume this to be the case in cells that maintain an
elevated signal flow, e.g. by oncogenic transformation.
Although the components that transfer the signal from
the site of DNA damage to the transcription factor are not
known, the elevated signal flow can be imitated: we and
others have found that activated oncogenes or elevated
expression of an oncogene can replace the need for the
stimulus, e.g. u.v. (Matrisian et al. 1986; Wasylyk et al.
1987; Schonthal et al. 1988a,6). Several cytoplasmic
oncogene products seem to participate in a signal transduction pathway terminating in the transcription factor
AP-1. Thus the elevated level of one of these oncogene
products causes part or all of the u.v. response.
Long-lasting consequences
It is obvious that DNA damage can cause permanent
genetic changes. If part or all of these were a consequence
of the u.v. response, it would need to be one of the
immediate and transient genetic changes that affect the
fate of the cell: amplified DNA and induced new gene
products.
The transiently induced program of DNA damageinduced genes includes a growing list of identified
functions. Transcription factors have been mentioned
(Angel et al. 1985). In addition to the activation of a
replication function acting on SV40, other replication
proteins are newly synthesized: DNA polymerase /5
(Fornace et al. 1989), perhaps DNA ligase (so far only
measured by enzyme activity: Mezzina et al. 1982). u.v.induced secreted proteases include plasminogen activator
(Miskin and Ben-Ishai, 1981) and collagenase (Angel et
al. 1986, 1987). There may also be various cell typespecific u.v. responsive genes (Kartasova and van de
Putte, 1988).
Among induced gene products, four have been identified that affect the cells' fate. This type of response
modification influences the fate of the cell in a subsequent
encounter with a DNA damaging agent. Several functions have been identified as being protective: metallothionein helps cells against alkylation toxicity (Kaina et
al. 1989a), mitochondrial manganese superoxide dismutase protects against part of oxygen radical toxicity (D. V.
Goeddel and G. H. W. Wong, unpublished). Radicalinduced heme oxygenase synthesis may also protect cells
(Keyse and Tyrrell, 1989). One of the most intriguing
consequences of the u.v. response is, in fact, the
increased risk of mutations and of transformation. Carcinogens and tumor promoters share a promoting effect
in the mouse skin carcinogenesis protocol. By fluctuation
analyses, induced states of 'mutation proneness', that is
an elevated chance to acquire a mutation several generations after contact with a mutagenic agent, have been
postulated (Kennedy et al. 1980; Maher e< a/. 1988). One
may even consider whether or not all mutations introduced by a mutagenic agent require the participation of
cellular 'mutator' functions. Evidence for their existence
has been obtained by turning the 'u.v. response' on in the
absence of DNA-damaging agents. For instance, elevated
oncogene expression (following the reasoning above)
imitates the signal flow to AP-1 and to other transcription
factors. The induced expression of ras, mos orfos causes
a 2- to 10-fold increase in chromosomal aberrations and
point mutations (unpublished). This suggests that
enhanced signal flow through normal components of
signal transduction can bring cells into a constant state of
an induced u.v. response or of tumor promotion. A
second method of inducing the u.v. response in the
absence of DNA damage has been applied, u.v.-treated
cells secrete one (or more) growth factor-like extracellular
'messenger' proteins (Schorpp et al. 1984; Rotem et al.
1987; this factor can prevent meaningful interpretations
of cell fusion experiments, as stated above). One of these
induces, in non-irradiated cells, most aspects of the u.v.
response, including HIV-1 and collagenase expression
and one or several mutator functions (Maher et al. 1988;
Stein et al. 19896). This factor is thus a candidate for
both long-term effects and spread of the effect within a
multicellular organism.
Finally, amplified DNA and induced retroviruses are
sources of genetic change. In order to enter a new cell
cycle and round of replication, excess material of locally
amplified DNA needs to be disconnected from the
chromosomes. We consider this material to be a substrate
for recombination enzymes that might cause permanent
genetic changes by integrating excess DNA into the
chromosomes. Retroviral DNA (e.g. HIV-1) has of
course evolved to cause proviral reintegrations that are
mutagenic.
components that recognize distorted DNA and the type
of signal passed on have not been clarified. What type of
post-translational modification occurs at the preformed
replication and transcription factors? How are chromosome and gene mutations generated? Knowing some of
the components involved, experiments can now be
designed to manipulate the u.v. response in the animal,
e.g. by deletion of genes, by depriving cells of labile
proteins by introduction of 'anti-sense' RNAs or by overexpression of identified genes. This will enable us to
challenge the in vivo significance of data and ideas
obtained so far in cell culture.
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