A mitosis-specific and R loop-driven ATR pathway promotes faithful chromosome segregation

Lilian Kabeche, Hai Dang Nguyen, Rémi Buisson, Lee Zou

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

The ataxia telangiectasia mutated and Rad3-related (ATR) kinase is crucial for DNA damage and replication stress responses. Here, we describe an unexpected role of ATR in mitosis. Acute inhibition or degradation of ATR in mitosis induces whole-chromosome missegregation. The effect of ATR ablation is not due to altered cyclin-dependent kinase 1 (CDK1) activity, DNA damage responses, or unscheduled DNA synthesis but to loss of an ATR function at centromeres. In mitosis, ATR localizes to centromeres through Aurora A-regulated association with centromere protein F (CENP-F), allowing ATR to engage replication protein A (RPA)-coated centromeric R loops. As ATR is activated at centromeres, it stimulates Aurora B through Chk1, preventing formation of lagging chromosomes. Thus, a mitosis-specific and R loop-driven ATR pathway acts at centromeres to promote faithful chromosome segregation, revealing functions of R loops and ATR in suppressing chromosome instability.

Original languageEnglish (US)
Pages (from-to)108-114
Number of pages7
JournalScience
Volume359
Issue number6371
DOIs
StatePublished - Jan 5 2018
Externally publishedYes

Bibliographical note

Funding Information:
We thank D. Compton for H2B-GFP–expressing RPE1 cells, N. Lowndes for the ATR−/−, AID-ATR DT40 cell line expressing degron-ATR, S. Taylor for the CENP-F C630 expression plasmid, and N. Dyson and members of the Zou and Dyson laboratories for discussions. L.K., H.D.N., and R.B. are supported by NIH fellowships 5T32CA009216-35, T32DK007540, and 1K99CA212154, respectively. L.Z. is the James and Patricia Poitras Endowed Chair in Cancer Research and is supported by the Jim and Ann Orr Massachusetts General Hospital Research Scholar Award. This work is supported by NIH grants (GM076388 and CA197779) to L.Z.

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