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

Isabelle Trier, Elizabeth M Black, Yoon Ki Joo, Lilian Kabeche

Cell reports 2023 May 30

filter terms:

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. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house the histone H3.3 chaperone DAXX (death domain-associated protein 6). We find that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A and an aberrant increase in H3.3 at interphase centromeres. Additionally, we show that ATR-dependent phosphorylation within the C terminus of DAXX regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, we demonstrate that acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Isabelle Trier, Elizabeth M Black, Yoon Ki Joo, Lilian Kabeche. ATR protects centromere identity by promoting DAXX association with PML nuclear bodies. Cell reports. 2023 May 30;42(5):112495