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 and Dipanjan Chowdhury ()
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Xiao-Feng Zheng: Dana-Farber Cancer Institute, Harvard Medical School
Sanket S. Acharya: Dana-Farber Cancer Institute, Harvard Medical School
Katherine N. Choe: Dana-Farber Cancer Institute, Harvard Medical School
Kumar Nikhil: Purdue University
Guillaume Adelmant: Dana-Farber Cancer Institute
Shakti Ranjan Satapathy: Purdue University
Samanta Sharma: Dana-Farber Cancer Institute
Keith Viccaro: Purdue University
Sandeep Rana: University of Nebraska Medical Center
Amarnath Natarajan: University of Nebraska Medical Center
Peter Sicinski: Dana-Farber Cancer Institute
Jarrod A. Marto: Dana-Farber Cancer Institute
Kavita Shah: Purdue University
Dipanjan Chowdhury: Dana-Farber Cancer Institute, Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12084-x

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