An efficient, accurate, and timely DNA damage response (DDR) is crucial for the maintenance of genome integrity. Here, we report that ten‐eleven translocation dioxygenase (TET) 3‐mediated conversion of 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC) in response to ATR‐dependent DDR regulates DNA repair. ATR‐dependent DDR leads to dynamic changes in 5hmC levels and TET3 enzymatic activity. We show that TET3 is an ATR kinase target that oxidizes DNA during ATR‐dependent DNA damage repair. Modulation of TET3 expression and activity affects DNA damage signaling and DNA repair and consequently cell death. Our results provide novel insight into ATR‐mediated DDR, in which TET3‐mediated DNA demethylation is crucial for efficient DNA repair and maintenance of genome stability.
An accurate and efficient DNA damage response is crucial for the maintenance of genome integrity. This study shows that TET3‐mediated DNA demethylation responds to DNA damage and promotes ATR‐dependent DNA damage signaling and repair.
DNA damage response (DDR) leads to changes in 5hmC levels.
DDR‐induced alterations in TET3 activity and 5hmC levels are ATR‐dependent.
TET3 is an ATR target and facilitates ATR‐dependent DNA damage signaling and repair.
Manipulation of TET3 activity affects DDR‐induced cell death and clonogenic survival.
- Received August 6, 2016.
- Revision received February 8, 2017.
- Accepted February 14, 2017.
- © 2017 The Authors
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