ATR protects centromere identity by promoting DAXX association with PML nuclear bodies.
Cell Rep
; 42(5): 112495, 2023 05 30.
Article
in En
| MEDLINE
| ID: mdl-37163376
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. 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Centromere
/
Promyelocytic Leukemia Nuclear Bodies
Type of study:
Risk_factors_studies
Language:
En
Journal:
Cell Rep
Year:
2023
Document type:
Article
Affiliation country:
Estados Unidos