Plk1 and CK2 Act in Concert to Regulate Rad51 during DNA Double Strand Break Repair

TLDR

Homologous recombination repairs DNA breaks during S and G2 phases, yet its regulatory mechanisms remain poorly understood. The study investigates how Polo-like kinase 1 phosphorylates Rad51 at serine 14 during the cell cycle and DNA damage. Plk1-mediated S14 phosphorylation permits CK2 to phosphorylate Rad51 at threonine 13, enabling direct binding to Nbs1. This phosphorylation cascade promotes Rad51 recruitment to damage sites, enhances resistance to genotoxic stress, and links Plk1 activity to HR repair and cancer development.

Abstract

Homologous recombination (HR) plays an important role in the maintenance of genome integrity. HR repairs broken DNA during S and G2 phases of the cell cycle but its regulatory mechanisms remain elusive. Here, we report that Polo-like kinase 1 (Plk1), which is vital for cell proliferation and is frequently upregulated in cancer cells, phosphorylates the essential Rad51 recombinase at serine 14 (S14) during the cell cycle and in response to DNA damage. Strikingly, S14 phosphorylation licenses subsequent Rad51 phosphorylation at threonine 13 (T13) by casein kinase 2 (CK2), which in turn triggers direct binding to the Nijmegen breakage syndrome gene product, Nbs1. This mechanism facilitates Rad51 recruitment to damage sites, thus enhancing cellular resistance to genotoxic stresses. Our results uncover a role of Plk1 in linking DNA damage recognition with HR repair and suggest a molecular mechanism for cancer development associated with elevated activity of Plk1.