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Thesis

French

ID: <

10670/1.7p45o5

>

Where these data come from
Function and Regulation of the DNA Polymerase Zeta during the DNA Replication : Consequences on Genome Stability.

Abstract

DNA replication is a fundamental process that ensures accurate duplication of the genetic information. Various perturbations can impede replication fork progression, and thus threatening genome integrity. To prevent fork collapse, replicative DNA polymerases can be replaced by error-prone DNA polymerases called translesion (TLS) polymerases, able to bypass DNA damage at the cost of increased mutations. Among TLS polymerases, Polζ is unique because inactivation of its catalytic subunit, REV3L, leads to embryonic lethality in mice underscoring its biological importance. However, little is known about its function and regulation in mammalian cells. We showed that loss of REV3L impairs S phase progression with a disruption of replication timing at specific genomic loci that replicate in mid-late S-phase, and this is associated with increased mutagenic events and aberrant epigenetic landscape. We also revealed that REV3L interacts with heterochromatin components and localizes in pericentromeric regions, suggesting that Polζ contributes to replicate heterochromatin regions to limit genome instability. In a second part, we discovered that REV3L protein is proteolytically processed by the endopeptidase TASP1 to generate two polypeptides that heterodimerize to form a stable complex that associates with REV7, likely representing the active complex of Polζ. We also found that REV3L is finely regulated in physiological conditions and after genotoxic stress at multiple levels: (1) transcriptionally, (2) proteolytically by TASP1 and (3) post-translationally by phosphorylation. Altogether these findings highlight a unique mechanism to control the function of an error-prone polymerase in mammalian cells. These data are particularly important given that Polζ is an important factor for tumor resistance to chemotherapeutic agents.

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