Abstract
ATR localized to centromeres to prevent lagging chromosomes independent of its role in replication stress.
Major finding: ATR localized to centromeres to prevent lagging chromosomes independent of its role in replication stress.
Mechanism: ATR engages centromeric R loops in mitosis to activate Aurora B via CHK1 to prevent lagging chromosomes.
Impact: ATR may be a therapeutic target in cancer cells vulnerable to chromosomal instability and replication stress.
The ATR kinase is an essential component of the response to DNA damage and replication stress, and loss of ATR during DNA replication increases genomic instability in S phase. Thus, ATR is a master regulator of genome integrity. Unexpectedly, Kabeche and colleagues found that ATR localized to centromeres on mitotic chromosomes, suggesting a potential role for ATR in chromosome segregation. Inhibition of ATR increased the rate of lagging chromosomes in anaphase, indicating a role for ATR in promoting accurate whole-chromosome segregation separate from its S-phase functions. Mechanistically, ATR phosphorylated CHK1 at centromeres, which subsequently activated Aurora B to facilitate correction of erroneous microtubule attachments at kinetochores. ATR localization to the mitotic centromeres was dependent on Aurora A, CENP-F, and R loops (DNA–RNA hybrids with a displaced single-stranded DNA), and ATR colocalized with RPA, which serves as a sensor for ssDNA in R loops. RPA-coated R loops generated by RNA polymerase II–mediated transcription during mitosis were detected at centromeres in mitotic cells and promoted ATR activation. R-loop stabilization facilitated ATR-mediated Aurora B activation and faithful chromosome segregation. Collectively, these findings reveal a role for ATR in promoting faithful chromosome segregation in mitosis to maintain genomic stability that is independent of its S-phase role in the DNA damage response. Further, these results suggest that ATR may be an effective therapeutic target in cancer cells that are vulnerable to defects in both chromosomal instability and replication stress.
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