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

Author:

Giunta SimonaORCID,Hervé SolèneORCID,White Ryan R.ORCID,Wilhelm ThereseORCID,Dumont Marie,Scelfo AndreaORCID,Gamba RiccardoORCID,Wong Cheng Kit,Rancati Giulia,Smogorzewska AgataORCID,Funabiki HironoriORCID,Fachinetti DanieleORCID

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.

Funder

HHS | NIH | National Institute of General Medical Sciences

Agence Nationale de la Recherche

National Research Foundation Singapore

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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