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

Simona Giunta (1) , Solène Hervé (2) , Ryan White (1, 2) , Therese Wilhelm (2) , Marie Dumont (2) , Andrea Scelfo (2) , Riccardo Gamba (2) , Cheng Kit Wong (3) , Giulia Rancati (3) , Agata Smogorzewska (1) , Hironori Funabiki (1) , Daniele Fachinetti (2)

1 Rockefeller University [New York]
2 Biologie Cellulaire et Cancer
3 A*STAR - Agency for science, technology and research [Singapore]

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Simona Giunta, Solène Hervé, Ryan White, Therese Wilhelm, Marie Dumont, et al.. CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy. Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (10), pp.e2015634118. ⟨10.1073/pnas.2015634118⟩. ⟨hal-03452717⟩