A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1

Nat Commun. 2019 Sep 18;10(1):4252. doi: 10.1038/s41467-019-12084-x.


Mitotic cells attenuate the DNA damage response (DDR) by phosphorylating 53BP1, a critical DDR mediator, to prevent its localization to damaged chromatin. Timely dephosphorylation of 53BP1 is critical for genome integrity, as premature recruitment of 53BP1 to DNA lesions impairs mitotic fidelity. Protein phosphatase 4 (PP4) dephosphorylates 53BP1 in late mitosis to allow its recruitment to DNA lesions in G1. How cells appropriately dephosphorylate 53BP1, thereby restoring DDR, is unclear. Here, we elucidate the underlying mechanism of kinetic control of 53BP1 dephosphorylation in mitosis. We demonstrate that CDK5, a kinase primarily functional in post-mitotic neurons, is active in late mitotic phases in non-neuronal cells and directly phosphorylates PP4R3β, the PP4 regulatory subunit that recognizes 53BP1. Specific inhibition of CDK5 in mitosis abrogates PP4R3β phosphorylation and abolishes its recognition and dephosphorylation of 53BP1, ultimately preventing the localization of 53BP1 to damaged chromatin. Our results establish CDK5 as a regulator of 53BP1 recruitment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 5 / metabolism*
  • DNA Damage / genetics
  • DNA Repair / genetics*
  • G1 Phase / genetics*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitosis / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*


  • RNA, Small Interfering
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Cyclin-Dependent Kinase 5
  • CDK5 protein, human
  • Phosphoprotein Phosphatases
  • protein phosphatase 4