PARP10 promotes the repair of nascent strand DNA gaps through RAD18 mediated translesion synthesis

Jude B. Khatib, Ashna Dhoonmoon, George-Lucian Moldovan and Claudia M. Nicolae ()
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Jude B. Khatib: The Pennsylvania State University College of Medicine
Ashna Dhoonmoon: The Pennsylvania State University College of Medicine
George-Lucian Moldovan: The Pennsylvania State University College of Medicine
Claudia M. Nicolae: The Pennsylvania State University College of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Replication stress compromises genomic integrity. Fork blocking lesions such as those induced by cisplatin and other chemotherapeutic agents arrest replication forks. Repriming downstream of these lesions represents an important mechanism of replication restart, however the single stranded DNA (ssDNA) gaps left behind, unless efficiently filled, can serve as entry point for nucleases. Nascent strand gaps can be repaired by BRCA-mediated homology repair. Alternatively, gaps can also be filled by translesion synthesis (TLS) polymerases. How these events are regulated is still not clear. Here, we show that PARP10, a poorly-characterized mono-ADP-ribosyltransferase, is recruited to nascent strand gaps to promote their repair. PARP10 interacts with the ubiquitin ligase RAD18 and recruits it to these structures, resulting in the ubiquitination of the replication factor PCNA. PCNA ubiquitination, in turn, recruits the TLS polymerase REV1 for gap filling. We show that PARP10 recruitment to gaps and the subsequent REV1-mediated gap filling requires both the catalytic activity of PARP10, and its ability to interact with PCNA. We moreover show that PARP10 is hyperactive in BRCA-deficient cells, and its inactivation potentiates gap accumulations and cytotoxicity in these cells. Our work uncovers PARP10 as a regulator of ssDNA gap filling, which promotes genomic stability in BRCA-deficient cells.

Date: 2024
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DOI: 10.1038/s41467-024-50429-3

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