Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
- 등재 SCIE, SCOPUS
- OA유형 Green Submitted, Green Published, gold
- 발행기관 Nature Research
- 발행년도 2023
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000208808
- 본문언어 영어
- Published As https://doi.org/10.1038/s41467-023-37480-2
- PubMed 36991019
초록/요약
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. © 2023, The Author(s).
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