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

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Science  23 Nov 2017:
eaan6490
DOI: 10.1126/science.aan6490

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Abstract

The ATR kinase is crucial for DNA damage and replication stress responses. Here, we describe a surprising 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 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 CENP-F, allowing ATR to engage 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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