Yale team: ATR kinase evicts CENP-A from centromeres under prolonged DNA damage in human and mouse cells
Authors report that prolonged genotoxic stress makes ATR kinase displace CENP-A to nucleoli via VCP, linking DNA damage to chromosomes that lack centromere identity.
A team from Yale University (New Haven and West Haven, USA), with Lilian Kabeche as corresponding author, has described a pathway that links DNA damage to centromere dysfunction. According to the paper in Nature Communications, published on 11 November 2026, prolonged exposure to genotoxic stress evicts the histone H3 variant CENP-A from centromeres. The displaced protein relocalizes to nucleoli. The effect was observed in both human and mouse cells. nature.com
Nature Communicationsnature.comOpen source ↗
Denis Ostapenko, Hang Li and Isabelle Trier contributed equally to the work. Earlier findings showed that DNA damage in interphase leads to genome instability in part by promoting missegregation of chromosomes that lack centromeres. The complete molecular mechanisms connecting damage to centromere dysfunction had remained incompletely understood.
ATR and VCP destabilize CENP-A nucleosomes
The process depends on ATR, a kinase of the DNA damage response. The authors report that ATR promotes the nuclear localization of the AAA+ ATPase VCP through phosphorylation of Ser784. This destabilizes nucleosomes that contain CENP-A and leads to its eviction from centromeres.
Nucleolar relocalization and segregation defects
The relocalization of evicted CENP-A to nucleoli relies on the nucleolar protein NPM1 and on HJURP, the canonical CENP-A chaperone. The H3 histone chaperones DAXX and ATRX are not required for this step. nature.com
Nature Communicationsnature.comOpen source ↗
ATR-dependent eviction of CENP-A persists after cells re-enter the cell cycle. It correlates with the emergence of CENP-A-deficient chromosomes, which, according to the authors, links DNA damage directly to segregation defects.
The authors state that the findings identify a role for ATR in regulating centromere identity under stress. They also describe a mechanistic pathway that contributes to genome instability. The experiments were performed in human and mouse cells.
