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State University of New York, Stony Brook

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Nucleic Acids Res., May 27 2024, gkae445 | https://doi.org/10.1093/nar/gkae445 The TIMELESS and PARP1 interaction suppresses replication-associated DNA gap accumulation

Joanne Saldanha^1,2, Julie Rageul ¹, Jinal A. Patel¹, Amy L. Phi ¹, Natalie Lo¹, Jennifer J. Park ¹ and Hyungjin Kim ^1,2,3,*

¹Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, NY 11794, USA

²The Graduate program in Genetics, State University of New York at Stony Brook, Stony Brook, NY 11794, USA

³Stony Brook Cancer Center, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794, USA

^*To whom correspondence should be addressed. : Hyungjin Kim

Abstract

TIMELESS (TIM) in the fork protection complex acts as a scaffold of the replisome to prevent its uncoupling and ensure efficient DNA replication fork progression. Nevertheless, its underlying basis for coordinating leading and lagging strand synthesis to limit single-stranded DNA (ssDNA) exposure remains elusive. Here, we demonstrate that acute degradation of TIM at ongoing DNA replication forks induces the accumulation of ssDNA gaps stemming from defective Okazaki fragment (OF) processing. Cells devoid of TIM fail to support the poly(ADP-ribosyl)ation necessary for backing up the canonical OF processing mechanism mediated by LIG1 and FEN1. Consequently, recruitment of XRCC1, a known effector of PARP1-dependent single-strand break repair, to post-replicative ssDNA gaps behind replication forks is impaired. Physical disruption of the TIM-PARP1 complex phenocopies the rapid loss of TIM, indicating that the TIM-PARP1 interaction is critical for the activation of this compensatory pathway. Accordingly, combined deficiency of FEN1 and the TIM-PARP1 interaction leads to synergistic DNA damage and cytotoxicity. We propose that TIM is essential for the engagement of PARP1 to the replisome to coordinate lagging strand synthesis with replication fork progression. Our study identifies TIM as a synthetic lethal target of OF processing enzymes that can be exploited for cancer therapy.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-30)
연구진국외 연구진
분야 생명과학 > 노화/암생물학

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