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

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Science  05 Jan 2018:
Vol. 359, Issue 6371, pp. 108-114
DOI: 10.1126/science.aan6490

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Mitosis-specific role of ATR

The ATR (ataxia telangiectasia mutated and Rad3-related) kinase plays important roles in the S phase and during the DNA damage response to safeguard genome integrity. Kabeche et al. identified a distinct ATR activation pathway in mitosis that is also critical for suppressing genome instability (see the Perspective by Saldivar and Cimprich). ATR is recruited by Aurora A and activated by R loops at centromeres of mitotic chromosomes; this leads to Aurora B activation, which is necessary for accurate chromosome segregation. This mitotic, R loop–driven ATR signaling pathway could potentially be exploited in the search for cancer therapeutics.

Science, this issue p. 108; see also p. 30

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.

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