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

Xiao Feng Zheng, Sanket S. Acharya, Katherine N. Choe, Kumar Nikhil, Guillaume Adelmant, Shakti Ranjan Satapathy, Samanta Sharma, Keith Viccaro, Sandeep Rana, Amarnath Natarajan, Peter Sicinski, Jarrod A. Marto, Kavita Shah, Dipanjan Chowdhury

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number4252
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Fingerprint

mitosis
phosphatases
Mitosis
DNA Repair
Chromatin
cascades
chromatin
Repair
deoxyribonucleic acid
proteins
lesions
DNA
cells
Neurons
Phosphotransferases
genome
Genes
regulators
neurons
integrity

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Zheng, X. F., Acharya, S. S., Choe, K. N., Nikhil, K., Adelmant, G., Satapathy, S. R., ... Chowdhury, D. (2019). A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. Nature communications, 10(1), [4252]. https://doi.org/10.1038/s41467-019-12084-x

A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. / Zheng, Xiao Feng; Acharya, Sanket S.; Choe, Katherine N.; Nikhil, Kumar; Adelmant, Guillaume; Satapathy, Shakti Ranjan; Sharma, Samanta; Viccaro, Keith; Rana, Sandeep; Natarajan, Amarnath; Sicinski, Peter; Marto, Jarrod A.; Shah, Kavita; Chowdhury, Dipanjan.

In: Nature communications, Vol. 10, No. 1, 4252, 01.12.2019.

Research output: Contribution to journalArticle

Zheng, XF, Acharya, SS, Choe, KN, Nikhil, K, Adelmant, G, Satapathy, SR, Sharma, S, Viccaro, K, Rana, S, Natarajan, A, Sicinski, P, Marto, JA, Shah, K & Chowdhury, D 2019, 'A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1', Nature communications, vol. 10, no. 1, 4252. https://doi.org/10.1038/s41467-019-12084-x
Zheng XF, Acharya SS, Choe KN, Nikhil K, Adelmant G, Satapathy SR et al. A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. Nature communications. 2019 Dec 1;10(1). 4252. https://doi.org/10.1038/s41467-019-12084-x
Zheng, Xiao Feng ; Acharya, Sanket S. ; Choe, Katherine N. ; Nikhil, Kumar ; Adelmant, Guillaume ; Satapathy, Shakti Ranjan ; Sharma, Samanta ; Viccaro, Keith ; Rana, Sandeep ; Natarajan, Amarnath ; Sicinski, Peter ; Marto, Jarrod A. ; Shah, Kavita ; Chowdhury, Dipanjan. / A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1. In: Nature communications. 2019 ; Vol. 10, No. 1.
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