Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 10, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2015634118
Keywords
CENP-A chromatin; DNA replication stress; chromosome translocations; genome instability; centromere
Categories
Funding
- Labex CelTisPhyBio
- Institut Curie
- ATIP-Avenir 2015 Program
- program Investissements d'Avenir
- Agence Nationale de la Recherche [ANR-17-CE12-0003, ANR-10-LABX-0038, ANR-10-IDEX-0001-02 PSL]
- Emergence Grant 2018 from the City of Paris
- Paris Sciences Lettres (PSL)
- Association pour la Recherche sur le Cancer (ARC) Foundation
- NIH [R35 GM132111, R01 GM121062]
- National Research Foundation Investigatorship [NRF-NRFI05-2019-0008]
- Merck Postdoctoral Fellowship Award
- National Institute of Diabetes and Digestive and Kidney Diseases National Research Service Award [5F32DK115144]
- Agence Nationale de la Recherche (ANR) [ANR-17-CE12-0003] Funding Source: Agence Nationale de la Recherche (ANR)
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The study demonstrates the importance of the centromere-specific histone H3 variant CENP-A in safeguarding DNA replication of alpha-satellite repeats to prevent structural aneuploidy during S phase, providing insights into how specialized centromeric chromatin maintains the integrity of transcribed noncoding repetitive DNA.
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.
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