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Nucleic Acids Res., Sep 18 2024, gkae785 | https://doi.org/10.1093/nar/gkae785 Polyubiquitinated PCNA triggers SLX4-mediated break-induced replication in alternative lengthening of telomeres (ALT) cancer cells

Sangin Kim^1,2, Su Hyung Park^1,3, Nalae Kang¹, Jae Sun Ra¹, Kyungjae Myung^1,3,* and Kyoo-young Lee^1,4,*

¹Center for Genomic Integrity, Institute for Basic Science, Ulsan 44919, Korea

²Department of Biological Sciences, College of Information-Bio Convergence Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea

³Department of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea

⁴Department of Biochemistry, College of Medicine, Hallym University, Chuncheon 24252, Gangwon-do, Republic of Korea

*To whom correspondence should be addressed. : Kyoo-young Lee

Correspondence may also be addressed to Kyungjae Myung.

Abstract

Replication stresses are the major source of break-induced replication (BIR). Here, we show that in alternative lengthening of telomeres (ALT) cells, replication stress-induced polyubiquitinated proliferating cell nuclear antigen (PCNA) (polyUb-PCNA) triggers BIR at telomeres and the common fragile site (CFS). Consistently, depleting RAD18, a PCNA ubiquitinating enzyme, reduces the occurrence of ALT-associated promyelocytic leukemia (PML) bodies (APBs) and mitotic DNA synthesis at telomeres and CFS, both of which are mediated by BIR. In contrast, inhibiting ubiquitin-specific protease 1 (USP1), an Ub-PCNA deubiquitinating enzyme, results in an increase in the above phenotypes in a RAD18- and UBE2N (the PCNA polyubiquitinating enzyme)-dependent manner. Furthermore, deficiency of ATAD5, which facilitates USP1 activity and unloads PCNAs, augments recombination-associated phenotypes. Mechanistically, telomeric polyUb-PCNA accumulates SLX4, a nuclease scaffold, at telomeres through its ubiquitin-binding domain and increases telomere damage. Consistently, APB increase induced by Ub-PCNA depends on SLX4 and structure-specific endonucleases. Taken together, our results identified the polyUb-PCNA-SLX4 axis as a trigger for directing BIR.

논문정보

형식Research article
게재일2024년 09월 (BRIC 등록일 2024-09-19)
연구진국내 연구진
분야 생명과학 > 분자생물학

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