ATR protects centromere identity by promoting DAXX association with PML nuclear bodies

Abstract

Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that Ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. As ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs) in unperturbed cells, we hypothesized that ATR protects CENP-A occupancy by regulating the localization of the histone H3.3 chaperone and PML NB component, DAXX. Indeed, we found that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A from interphase centromeres. Lastly, we demonstrate that CENP-A occupancy is not restored until G1 of the following cell cycle, leading to increased mitotic chromosome segregation defects. These findings demonstrate a novel mechanism by which ATR protects centromere identity and genome stability.