PT  - JOURNAL ARTICLE
AU  - Valentina Palermo
AU  - Eva Malacaria
AU  - Massimo Sanchez
AU  - Annapaola Franchitto
AU  - Pietro Pichierri
TI  - Switch-Like Phosphorylation of Wrn Integrates End-Resection With Repair of Dsbs at Replication Forks
AID  - 10.1101/403808
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 403808
4099  - http://biorxiv.org/content/early/2018/08/29/403808.short
4100  - http://biorxiv.org/content/early/2018/08/29/403808.full
AB  - 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 to conclude long-range end-resection and support 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.