Abstract

Abstract The replisome faithfully coordinates the essential process of genome duplication despite genomic sequences or lesions that slow or stall replication fork progression, collectively termed replication stress. Such lesions threaten the accurate transmission of the genome; as such, cells have evolved many mechanisms of replication fork protection and repair to ensure that the genome is fully replicated within the confines of S phase. Our group has previously characterized the essential protein Replication Termination Factor 2 (RTF2) as one such facilitator of replication control during both unperturbed and stalled conditions. During unperturbed replication, RTF2 localizes the Ribonuclease H2 heterotrimer (RNase H2) to replication forks, where RNase H2 facilitates the removal of ribonucleotides aberrantly incorporated into the genome to ensure replication fork speeds and promote the completion of genome duplication. When the replisome encounters fork-stalling lesions, however, RTF2-RNase H2 are removed from the replisome through the action of proteasome shuttle proteins DNA Damage Inducible 1 and 2 (DDI1/2) to promote replication restart dependent upon PRIM1, the primase subunit of DNA polymerase α. Further, we find that cells depleted of RTF2 accumulate mitotic markers, including phosphorylated FOXM1 and cyclin B1, during S phase and exhibit abnormal nuclear structures. Together, these findings suggest that RTF2-deficient cells bypass the S/G2 checkpoint, in which ATR functions to suppress CDK1 activity and mitotic progression while replication is ongoing and implicate RTF2 as a mediator of replication checkpoint control. Citation Format: Agata Smogorzewska, Cayla Broton, Nicolas J. Blobel, Brooke Conti. The role of RTF2 in replication and replication stress response [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA023.

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