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Implication de l’ADN polymérase spécialisée zêta au cours de la réplication de l’hétérochromatine dans les cellules de mammifères

Abstract : DNA polymerase zeta (Polζ) is a key player in Translesion DNA synthesis (TLS). Polζ is unique among TLS polymerases in mammalian cells, because inactivation of the gene encoding its catalytic subunit (Rev3L) leads to embryonic lethality in the mouse. However little is known about its biological functions under normal growth conditions.Here we show that S phase progression is impaired in Rev3L-/- MEFs with a delay in mid and late S phase. Genome-wide profiling of replication timing revealed that Rev3L inactivation induces changes in the temporal replication program, mainly in particular genomic regions in which the replication machinery propagates a slower velocity. We also highlighted a global enrichment of repressive histone modifications as well as hypermethylation of major satellites DNA repeats in Rev3L-deficient cells, suggesting that fork movements can slow down or stall in specific locations, and a delay in restarting forks could promote heterochromatin formation in Rev3L-depleted cells. As a direct or indirect consequence, we found that several genes involved in growth and development are down-regulated in Rev3L-/- MEFs, which might potentially explain the embryonic lethality observed in Rev3L KO mice. Finally we discovered that HP1α directly interacts and recruits Rev3L to pericentromeric heterochromatin. We therefore propose that Polζ has been co-opted by evolution to assist DNA polymerase ε and δ in duplicating condensed chromatin domains during mid and late S phase.
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Sana Ahmed-Seghir. Implication de l’ADN polymérase spécialisée zêta au cours de la réplication de l’hétérochromatine dans les cellules de mammifères. Biologie cellulaire. Université Paris Sud - Paris XI, 2015. Français. ⟨NNT : 2015PA11T052⟩. ⟨tel-01880505⟩

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