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Proc. Natl. Acad. Sci. USA, Aug 20 2024, 121 (34) | https://doi.org/10.1073/pnas.2315759121 ATAD5 functions as a regulatory platform for Ub-PCNA deubiquitination

Eunjin Ryu^a,b,1,2, Juyeong Yoo^a,b,2, Mi-Sun Kang^a,2, Na Young Ha^a, Yewon Jang^a,c, Jinwoo Kim^a, Yeongjae Kim^a,b, Byung-Gyu Kim^a, Shinseog Kim^a, Kyungjae Myung^a,c, and Sukhyun Kang^a,3

^aCenter for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea

^bDepartment of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea

^cDepartment of Biomedical Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea

¹Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215

²E.R., J.Y., and M.-S.K. contributed equally to this work.

³To whom correspondence may be addressed. : Sukhyun Kang

Abstract

Ubiquitination status of proliferating cell nuclear antigen (PCNA) is crucial for regulating DNA lesion bypass. After the resolution of fork stalling, PCNA is subsequently deubiquitinated, but the underlying mechanism remains undefined. We found that the N-terminal domain of ATAD5 (ATAD5-N), the largest subunit of the PCNA-unloading complex, functions as a scaffold for Ub-PCNA deubiquitination. ATAD5 recognizes DNA-loaded Ub-PCNA through distinct DNA-binding and PCNA-binding motifs. Furthermore, ATAD5 forms a heterotrimeric complex with UAF1-USP1 deubiquitinase, facilitating the deubiquitination of DNA-loaded Ub-PCNA. ATAD5 also enhances the Ub-PCNA deubiquitination by USP7 and USP11 through specific interactions. ATAD5 promotes the distinct deubiquitination process of UAF1-USP1, USP7, and USP11 for poly-Ub-PCNA. Additionally, ATAD5 mutants deficient in UAF1-binding had increased sensitivity to DNA-damaging agents. Our results ultimately reveal that ATAD5 and USPs cooperate to efficiently deubiquitinate Ub-PCNA prior to its release from the DNA in order to safely deactivate the DNA repair process.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-22)
연구진국내 연구진
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