Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance. Academic Article uri icon

Overview

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.

publication date

  • March 29, 2023

Research

keywords

  • F-Box Proteins
  • Neoplasms
  • Telomerase

Identity

PubMed Central ID

  • PMC10060224

Scopus Document Identifier

  • 85151203686

Digital Object Identifier (DOI)

  • 10.1038/nbt.1587

PubMed ID

  • 36991019

Additional Document Info

volume

  • 14

issue

  • 1