ARID1A promotes genomic stability through protecting telomere cohesion

Bo Zhao, Jianhuang Lin, Lijie Rong, Shuai Wu, Zhong Deng, Nail Fatkhutdinov, Joseph Zundell, Takeshi Fukumoto, Qin Liu, Andrew Kossenkov, Stephanie Jean, Mark G. Cadungog, Mark E. Borowsky, Ronny Drapkin, Paul M. Lieberman, Cory T. Abate-Shen and Rugang Zhang ()
Additional contact information
Bo Zhao: The Wistar Institute
Jianhuang Lin: The Wistar Institute
Lijie Rong: Columbia University Irving Medical Center
Shuai Wu: The Wistar Institute
Zhong Deng: The Wistar Institute
Nail Fatkhutdinov: The Wistar Institute
Joseph Zundell: The Wistar Institute
Takeshi Fukumoto: The Wistar Institute
Qin Liu: The Wistar Institute
Andrew Kossenkov: The Wistar Institute
Stephanie Jean: Helen F. Graham Cancer Center & Research Institute
Mark G. Cadungog: Helen F. Graham Cancer Center & Research Institute
Mark E. Borowsky: Helen F. Graham Cancer Center & Research Institute
Ronny Drapkin: University of Pennsylvania
Paul M. Lieberman: The Wistar Institute
Cory T. Abate-Shen: Columbia University Irving Medical Center
Rugang Zhang: The Wistar Institute

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12037-4

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