Journées jeunes chercheurs en cancérologie
CONFÉRENCE SCIENTIFIQUE
Genotoxic metabolic by-products and cellular
responses to DNA replication obstacles
The rate of spontaneous alterations in the chemical structure of DNA
and the number of impediments to the progression of DNA replication
forks are chronically elevated in cancer cells. Thus, cancer cells evolve along
with genotoxic stress support pathway that allow cell proliferation in the
continuous presence of high levels of DNA damage. This hallmark feature
of cancer cells can be exploited via genotoxic stress sensitization.
Dr Angelos Constantinou
Institut de génétique humaine (Montpellier)
Leaders de demain Fondation ARC 2010
© Noak/Le Bar Floréal/Fondation ARC
We study how cells respond to replication impediments. Our goal is to unveil
novel mechanisms that allow DNA replication to overcome obstacles. We
believe that these mechanisms are key determinants of tumor growth and
resistance to chemotherapies. In recent years, our main focus has been on
the molecular function of proteins implicated in Fanconi anemia, a genetic
disorder characterized by congenital abnormalities, bone marrow failure
and cancer proneness. FANC proteins are necessary to coordinate the
action of molecular machines involved in the rescue of stalled replication
forks and in DNA repair. We explore novel mechanisms implicated in the
signaling of damaged replication intermediates, and we use proteomic
approaches to understand the biology of the replication machinery under
stressful conditions.
This presentation will be focused on our recent findings that dihydropyrimidines accumulation in cancer cells induce replication-blocking
lesions halting cell proliferation. Our interest in dihydropyrimidines has
its origin in a yeast two hybrid screen for proteins that interact with
FANCM, a multifunctional DNA translocase that ensures chromosomal
stability during DNA replication. We found that FANCM associates with
dihydropyrimidinase. We will show evidence that suppression of dihydropyrimidinase in cancer cells induce sufficient amounts of dihydropyrimidines to severely impair the progression of replication forks, induce
replication stress signalling, the accumulation of p53, and eventually
block cell proliferation.
In healthy individuals, expression of dihydropyrimidinase is normally
restricted to the liver and the kidney. Dihydropyrimidinase, however, is reexpressed in a variety of carcinoma. Hence, dihydropyrimidinase appears a
candidate target to selectively block the growth of carcinoma.
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