RTF2 controls replication repriming and ribonucleotide excision at the replisome.

TitleRTF2 controls replication repriming and ribonucleotide excision at the replisome.
Publication TypeJournal Article
Year of Publication2023
AuthorsConti BA, Ruiz PD, Broton C, Blobel NJ, Kottemann MC, Sridhar S, Lach FP, Wiley T, Sasi NK, Carroll T, Smogorzewska A
JournalbioRxiv
Date Published2023 Mar 13
Abstract

Genetic information is duplicated via the highly regulated process of DNA replication. The machinery coordinating this process, the replisome, encounters many challenges, including replication fork-stalling lesions that threaten the accurate and timely transmission of genetic information. Cells have multiple mechanisms to repair or bypass lesions that would otherwise compromise DNA replication 1,2 . We have previously shown that proteasome shuttle proteins, DNA Damage Inducible 1 and 2 (DDI1/2) function to regulate Replication Termination Factor 2 (RTF2) at the stalled replisome, allowing for replication fork stabilization and restart 3 . Here we show that RTF2 regulates replisome localization of RNase H2, a heterotrimeric enzyme responsible for removing RNA in the context of RNA-DNA heteroduplexes 4-6 . We show that during unperturbed DNA replication, RTF2, like RNase H2, is required to maintain normal replication fork speeds. However, persistent RTF2 and RNase H2 at stalled replication forks compromises the replication stress response, preventing efficient replication restart. Such restart is dependent on PRIM1, the primase component of DNA polymerase α-primase. Our data show a fundamental need for regulation of replication-coupled ribonucleotide incorporation during normal replication and the replication stress response that is achieved through RTF2. We also provide evidence for PRIM1 function in direct replication restart following replication stress in mammalian cells.

DOI10.1101/2023.03.13.532415
Alternate JournalbioRxiv
PubMed ID36993543
PubMed Central IDPMC10054921
Grant ListF30 CA268717 / CA / NCI NIH HHS / United States

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