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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 LU ; Sharma, Samanta ; Viccaro, Keith ; Rana, Sandeep and Natarajan, Amarnath , et al. (2019) In Nature Communications 10(1). p.1-13
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
keywords
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
in
Nature Communications
volume
10
issue
1
article number
4252
pages
1 - 13
publisher
Nature Publishing Group
external identifiers
  • pmid:31534152
  • scopus:85072383591
ISSN
2041-1723
DOI
10.1038/s41467-019-12084-x
language
English
LU publication?
no
id
c6c402db-45de-498e-878b-72cf8c471c58
date added to LUP
2025-01-30 10:24:42
date last changed
2025-04-25 10:12:19
@article{c6c402db-45de-498e-878b-72cf8c471c58,
  abstract     = {{<p>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.</p>}},
  author       = {{Zheng, Xiao-Feng and Acharya, Sanket S and Choe, Katherine N and Nikhil, Kumar and Adelmant, Guillaume and Satapathy, Shakti Ranjan and Sharma, Samanta and Viccaro, Keith and Rana, Sandeep and Natarajan, Amarnath and Sicinski, Peter and Marto, Jarrod A and Shah, Kavita and Chowdhury, Dipanjan}},
  issn         = {{2041-1723}},
  keywords     = {{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}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{1}},
  pages        = {{1--13}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{A mitotic CDK5-PP4 phospho-signaling cascade primes 53BP1 for DNA repair in G1}},
  url          = {{http://dx.doi.org/10.1038/s41467-019-12084-x}},
  doi          = {{10.1038/s41467-019-12084-x}},
  volume       = {{10}},
  year         = {{2019}},
}