Molecular Cell
Volume 40, Issue 3, 12 November 2010, Pages 377-387
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Article
A Shld1-Controlled POT1a Provides Support for Repression of ATR Signaling at Telomeres through RPA Exclusion

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Summary

We previously proposed that POT1 prevents ATR signaling at telomeres by excluding RPA from the single-stranded TTAGGG repeats. Here, we use a Shld1-stabilized degron-POT1a fusion (DD-POT1a) to study the telomeric ATR kinase response. In the absence of Shld1, DD-POT1a degradation resulted in rapid and reversible activation of the ATR pathway in G1 and S/G2. ATR signaling was abrogated by shRNAs to ATR and TopBP1, but shRNAs to the ATM kinase or DNA-PKcs did not affect the telomere damage response. Importantly, ATR signaling in G1 and S/G2 was reduced by shRNAs to RPA. In S/G2, RPA was readily detectable at dysfunctional telomeres, and both POT1a and POT1b were required to exclude RPA and prevent ATR activation. In G1, the accumulation of RPA at dysfunctional telomeres was strikingly less, and POT1a was sufficient to repress ATR signaling. These results support an RPA exclusion model for the repression of ATR signaling at telomeres.

Highlights

► A Shld1-dependent POT1a allows rapid and reversible deprotection of telomeres ► Loss of POT1 protection activates RPA- and TopBP1-dependent ATR kinase signaling ► RPA accumulates at deprotected telomeres in S/G2 but less so in G1 ► Distinct requirements for POT1a in S/G2 and G1 support an RPA exclusion model

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