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.
Highlights
When examining chromosome spreads in prometaphase mitotic shake-off cells, we discovered that compared with ARID1A wildtype ovarian clear cell carcinomas (OCCCs) RMG1 parental controls, isogenic ARID1A knockout (KO) RMG1 cells displayed a significant increase in the distance between distal ends of sister chromatids (Fig. 1a, b)
We show that ARID1A plays a critical role in telomere cohesion and ARID1A inactivation serves as a negative selection to preserve genomic stability
It was not linked to ARID1A mutational status, previous studies indicate the presence of two distinct clusters of OCCC based on their copy number changes[17]
Summary
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. ARID1A inactivation leads to activation of the decatenation checkpoint and polyploidy in vitro[7,8] These functions of ARID1A would predict large-scale genomic alterations and aneuploidy in ARID1A-mutated cancers caused by mitotic defects. Compared with ARID1A wild-type tumors, ARID1A-mutated tumors display significantly less genomic instability as measured by CNA across multiple cancer types Together, these results show that ARID1A inactivation is selective against gross chromosome aberrations through causing defects in telomere cohesion
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