ARID1A promotes genomic stability through protecting telomere cohesion

Nat Commun. 2019 Sep 6;10(1):4067. doi: 10.1038/s41467-019-12037-4.

Abstract

ARID1A inactivation causes mitotic defects. Paradoxically, cancers with high ARID1A mutation rates typically lack copy number alterations (CNAs). Here, we show that ARID1A inactivation causes defects in telomere cohesion, which selectively eliminates gross chromosome aberrations during mitosis. ARID1A promotes the expression of cohesin subunit STAG1 that is specifically required for telomere cohesion. ARID1A inactivation causes telomere damage that can be rescued by STAG1 expression. Colony formation capability of single cells in G2/M, but not G1 phase, is significantly reduced by ARID1A inactivation. This correlates with an increase in apoptosis and a reduction in tumor growth. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less CNAs across multiple cancer types. Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion, which reconciles the long-standing paradox between the role of ARID1A in maintaining mitotic integrity and the lack of genomic instability in ARID1A-mutated cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Cohesins
  • DNA Copy Number Variations
  • DNA-Binding Proteins
  • Female
  • Genomic Instability*
  • Humans
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Telomere / genetics*
  • Telomere / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transplantation, Heterologous / methods
  • Tumor Burden / genetics

Substances

  • ARID1A protein, human
  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Transcription Factors