CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy
- 2 March 2021
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 118 (10)
- https://doi.org/10.1073/pnas.2015634118
Abstract
Chromosome segregation relies on centromeres, yet their repetitive DNA is often prone to aberrant rearrangements under pathological conditions. Factors that maintain centromere integrity to prevent centromere-associated chromosome translocations are unknown. Here, we demonstrate the importance of the centromere-specific histone H3 variant CENP-A in safeguarding DNA replication of alpha-satellite repeats to prevent structural aneuploidy. Rapid removal of CENP-A in S phase, but not other cell-cycle stages, caused accumulation of R loops with increased centromeric transcripts, and interfered with replication fork progression. Replication without CENP-A causes recombination at alpha-satellites in an R loop-dependent manner, unfinished replication, and anaphase bridges. In turn, chromosome breakage and translocations arise specifically at centromeric regions. Our findings provide insights into how specialized centromeric chromatin maintains the integrity of transcribed noncoding repetitive DNA during S phase.Keywords
Funding Information
- HHS | NIH | National Institute of General Medical Sciences (R35GM132111)
- HHS | NIH | National Institute of General Medical Sciences (R01GM121062)
- Agence Nationale de la Recherche (ANR-10-LABX-0038)
- Agence Nationale de la Recherche (ANR-10-IDEX-0001-02 PSL)
- National Research Foundation Singapore (NRF-NRFI05-2019-0008)
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (5F32DK115144)
- Agence Nationale de la Recherche (ANR-17-CE12-0003)
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