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

ARID1A promotes genomic stability through protecting telomere cohesion.

Author information

1
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
2
Department of Pharmacology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, 10032, USA.
3
Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, 19104, USA.
4
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA, 19104, USA.
5
Helen F. Graham Cancer Center & Research Institute, Newark, DE, 19713, USA.
6
Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
7
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, 19104, USA. rzhang@wistar.org.

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.

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