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bioRxiv · 10.1101/403808

SWITCH-LIKE PHOSPHORYLATION OF WRN INTEGRATES END-RESECTION WITH REPAIR OF DSBs AT REPLICATION FORKS

Palermo, V.·Malacaria, E.·Sanchez, M.·Franchitto, A.·Pichierri, P.
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Abstract

Replication-dependent DNA double-strand breaks are harmful lesions preferentially repaired by homologous recombination; a process that requires processing of DNA ends to allow RAD51-mediated strand invasion. End-resection and subsequent repair are two intertwined processes, but the mechanism underlying their execution is still poorly appreciated. The WRN helicase is one of the crucial factors for the end-resection and is instrumental to select the proper repair pathway. Here, we reveal that ordered phosphorylation of WRN by the CDK1, ATM and ATR kinases define a complex regulatory layer that is essential for correct long-range end-resection connecting it to repair by homologous recombination. We establish that long-range end-resection requires an ATM-dependent phosphorylation of WRN at Ser1058 and that phosphorylation at Ser1141, together with dephosphorylation at the CDK1 site Ser1133, is needed for the correct metabolism of RAD51 foci and RAD51-dependent repair. Collectively, our findings suggest that regulation of WRN by multiple kinases functions as molecular switch to allow a timely execution of end-resection and repair at replication-dependent DNA double-strand breaks.

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Palermo, V., Malacaria, E., Sanchez, M., Franchitto, A., Pichierri, P.. 2018-08-29. SWITCH-LIKE PHOSPHORYLATION OF WRN INTEGRATES END-RESECTION WITH REPAIR OF DSBs AT REPLICATION FORKS. https://doi.org/10.1101/403808

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