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Nucleic Acids Res., Sep 15 2023, gkad732 | https://doi.org/10.1093/nar/gkad732 OTUD5 limits replication fork instability by organizing chromatin remodelers

Angelo de Vivo ¹, Hongseon Song ², Yujin Lee ², Neysha Tirado-Class ¹, Anthony Sanchez ¹, Sandy Westerheide ¹, Huzefa Dungrawala ¹, Younghoon Kee ^1,2

¹Department of Molecular Biosciences, College of Arts and Sciences, University of South Florida, Tampa, FL 33647, USA.

²Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno-Joongang-daero, Dalseong-gun, Daegu 42988, Republic of Korea.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as Joint First Authors.

To whom correspondence should be addressed. : Younghoon Kee

Abstract

Proper regulation of replication fork progression is important for genomic maintenance. Subverting the transcription-induced conflicts is crucial in preserving the integrity of replication forks. Various chromatin remodelers, such as histone chaperone and histone deacetylases are known to modulate replication stress, but how these factors are organized or collaborate are not well understood. Here we found a new role of the OTUD5 deubiquitinase in limiting replication stress. We found that OTUD5 is recruited to replication forks, and its depletion causes replication fork stress. Through its C-terminal disordered tail, OTUD5 assembles a complex containing FACT, HDAC1 and HDAC2 at replication forks. A cell line engineered to specifically uncouple FACT interaction with OTUD5 exhibits increases in FACT loading onto chromatin, R-loop formation, and replication fork stress. OTUD5 mediates these processes by recruiting and stabilizing HDAC1 and HDAC2, which decreases H4K16 acetylation and FACT recruitment. Finally, proteomic analysis revealed that the cells with deficient OTUD5-FACT interaction activates the Fanconi Anemia pathway for survival. Altogether, this study identified a new interaction network among OTUD5-FACT-HDAC1/2 that limits transcription-induced replication stress.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-19)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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