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

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.