ARID1A promotes genomic stability through protecting telomere cohesion
| Autor: | Rugang Zhang, Bo Zhao, Nail Fatkhutdinov, Cory Abate-Shen, Ronny Drapkin, Qin Liu, Takeshi Fukumoto, Jianhuang Lin, Lijie Rong, Mark E. Borowsky, Stephanie Jean, Joseph A. Zundell, Shuai Wu, Andrew V. Kossenkov, Mark G. Cadungog, Zhong Deng, Paul M. Lieberman |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Genome instability Mutation rate ARID1A Chromosomal Proteins Non-Histone General Physics and Astronomy Apoptosis Cell Cycle Proteins 02 engineering and technology Mice SCID Mice Inbred NOD lcsh:Science Cancer genetics Mice Knockout Ovarian Neoplasms Multidisciplinary Nuclear Proteins Telomere 021001 nanoscience & nanotechnology 3. Good health Cell biology Tumor Burden DNA-Binding Proteins Female 0210 nano-technology DNA Copy Number Variations Science Transgene Transplantation Heterologous Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology Genomic Instability Article Cell Line 03 medical and health sciences Ovarian cancer Cell Line Tumor Animals Humans Mitosis Cohesin General Chemistry Transplantation 030104 developmental biology Mutation lcsh:Q Transcription Factors |
| Zdroj: | Nature Communications Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2041-1723 |
| Popis: | 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. Cells with ARID1A mutations exhibit mitotic defects, yet show surprisingly low levels of copy number defects. Here, Zhao et al. resolve this issue by showing that ARID1A loss causes defects in telomere cohesion, which selects against gross alterations in copy number. |
| Databáze: | OpenAIRE |
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