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

Proceedings of the National Academy of Sciences
Simona Giunta, Solène Hervé, Ryan R. White, Therese Wilhelm, Marie Dumont, Andrea Scelfo, Riccardo Gamba, Cheng Kit Wong, Giulia Rancati, Agata Smogorzewska, Hironori Funabiki, Daniele Fachinetti
DOI
10.1073/pnas.2015634118
Abstract

Significance
CENP-A, the histone H3 variant that forms a unique centromeric chromatin, is essential for faithful chromosome segregation during mitosis. Inability to connect the centromere to the mitotic spindle causes aneuploidy, a hallmark of many cancers. In addition to chromosome missegregation, chromosome fusions at (peri)centromeres are prevalent in cancers, but how such rearrangements arise remains unclear. Here, we identified a role for CENP-A in maintaining the integrity of centromere-associated repetitive sequences by ensuring their effective replication in human cells. In the absence of CENP-A, generation of DNA–RNA hybrids due to transcription–replication conflicts causes delayed DNA replication, centromere breakage, recombination, and chromosome translocations at centromeres. Centromeres thus possess a special mechanism to facilitate their replication and suppress chromosome translocations.

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