한빛사논문
- 조회899
Fei Li1,2,9, Yizhe Wang3,9, Inah Hwang3,4,9, Ja-Young Jang3, Libo Xu2,5, Zhong Deng6, Eun Young Yu7, Yiming Cai8, Caizhi Wu2, Zhenbo Han8, Yu-Han Huang2, Xiangao Huang3, Ling Zhang2,5, Jun Yao8, Neal F. Lue7, Paul M. Lieberman6, Haoqiang Ying8, Jihye Paik3 & Hongwu Zheng3
1Department of Neurosurgery, Southwest Hospital, Chongqing 400038, China.
2Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
3Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
4Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
5Key Laboratory of Pathobiology, Ministry of Education, and Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China.
6The Wistar Institute, Philadelphia, PA 19104, USA.
7Department of Microbiology and Immunology, W. R. Hearst Microbiology Research Center, Weill Cornell Medicine, New York, NY 10065, USA.
8Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
9These authors contributed equally: Fei Li, Yizhe Wang, Inah Hwang.
Corresponding authors : Correspondence to Jihye Paik or Hongwu Zheng.
Abstract
Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% − 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following recombination-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-31)
- 국내+국외 연구진
- 의약학 > 분자세포의학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
연구자 ID
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
