CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy

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 th...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-03, Vol.118 (10), p.1
Main Authors: Giunta, Simona, Hervé, Solène, White, Ryan R, Wilhelm, Therese, Dumont, Marie, Scelfo, Andrea, Gamba, Riccardo, Wong, Cheng Kit, Rancati, Giulia, Smogorzewska, Agata, Funabiki, Hironori, Fachinetti, Daniele
Format: Article
Language:English
Subjects:
Anaphase
Aneuploidy
Biochemistry, Molecular Biology
Biological Sciences
Cell Line
Centromere - genetics
Centromere - metabolism
Centromere protein A
Centromere Protein A - genetics
Centromere Protein A - metabolism
Centromeres
Chromatin
Chromatin - genetics
Chromatin - metabolism
Chromosome translocations
Chromosomes
Chromosomes, Human - genetics
Chromosomes, Human - metabolism
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA Replication
Genomics
Histone H3
Histones
Humans
Integrity
Life Sciences
Recombination
Replication
S Phase
Satellite DNA
Satellites
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2015634118