PLK1 phosphorylates WRN at replication forks

Prostate cancer, particularly castration-resistant prostate cancer, remains a serious public health issue. Androgen signaling inhibitors have emerged as a major treatment approach but with limited success. Thus, identification of novel treatment targets is of high clinical relevance. Polo-like kinase 1 (PLK1) has documented roles in various aspects of prostate cancer, including resistance to androgen inhibitors. Radiotherapy is another major approach for treating prostate cancer, but how Plk1 might regulate the efficacy of radiotherapy is unknown. Nonhomologous end joining (NHEJ) and homologous recombination (HR) are 2 major DNA repair pathways, with cellular choices between NHEJ and HR being elegantly regulated by end-processing. However, how the long-range DNA end resection is regulated remains poorly understood. It has been documented that Werner syndrome protein (WRN) is actively involved in the long-range resection pathway. In this study, we demonstrate that PLK1-associated phosphorylation of WRN regulates end resection at double-strand breaks, thereby promoting HR and chromosome stability. Cells expressing the WRN nonphosphorylatable mutant show the phenotype similar to WRN null cells because they lack the ability for long-range resection and increase NHEJ. In summary, we reveal that PLK1-associated Mre11, Rad50 and Nbs1 phosphorylation promotes end resection, eventually affecting cellular choices for double-strand break repair pathways. Significance Statement: Both DNA damage repair and PLK1 play critical roles in the efficacy of radiotherapy of prostate cancer. The data presented here will provide guidance on how to manipulate PLK1 to improve the efficacy of radiotherapy in clinical settings.