UBE2D3 facilitates NHEJ by orchestrating ATM signalling through multi-level control of RNF168

Zeliha Yalçin, Shiu Yeung Lam, Marieke H. Peuscher, Jaco Torre, Sha Zhu, Prasanna V. Iyengar, Daniel Salas-Lloret, Inge Krijger, Nathalie Moatti, Ruben Lugt, Mattia Falcone, Aurora Cerutti, Onno B. Bleijerveld, Liesbeth Hoekman, Román González-Prieto and Jacqueline J. L. Jacobs ()
Additional contact information
Zeliha Yalçin: The Netherlands Cancer Institute
Shiu Yeung Lam: The Netherlands Cancer Institute
Marieke H. Peuscher: The Netherlands Cancer Institute
Jaco Torre: The Netherlands Cancer Institute
Sha Zhu: The Netherlands Cancer Institute
Prasanna V. Iyengar: The Netherlands Cancer Institute
Daniel Salas-Lloret: Leiden University Medical Center
Inge Krijger: The Netherlands Cancer Institute
Nathalie Moatti: The Netherlands Cancer Institute
Ruben Lugt: The Netherlands Cancer Institute
Mattia Falcone: The Netherlands Cancer Institute
Aurora Cerutti: The Netherlands Cancer Institute
Onno B. Bleijerveld: The Netherlands Cancer Institute
Liesbeth Hoekman: The Netherlands Cancer Institute
Román González-Prieto: Leiden University Medical Center
Jacqueline J. L. Jacobs: The Netherlands Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Maintenance of genome integrity requires tight control of DNA damage response (DDR) signalling and repair, with phosphorylation and ubiquitination representing key elements. How these events are coordinated to achieve productive DNA repair remains elusive. Here we identify the ubiquitin-conjugating enzyme UBE2D3 as a regulator of ATM kinase-induced DDR that promotes non-homologous end-joining (NHEJ) at telomeres. UBE2D3 contributes to DDR-induced chromatin ubiquitination and recruitment of the NHEJ-promoting factor 53BP1, both mediated by RNF168 upon ATM activation. Additionally, UBE2D3 promotes NHEJ by limiting RNF168 accumulation and facilitating ATM-mediated phosphorylation of KAP1-S824. Mechanistically, defective KAP1-S824 phosphorylation and telomeric NHEJ upon UBE2D3-deficiency are linked to RNF168 hyperaccumulation and aberrant PP2A phosphatase activity. Together, our results identify UBE2D3 as a multi-level regulator of NHEJ that orchestrates ATM and RNF168 activities. Moreover, they reveal a negative regulatory circuit in the DDR that is constrained by UBE2D3 and consists of RNF168- and phosphatase-mediated restriction of KAP1 phosphorylation.

Date: 2024
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DOI: 10.1038/s41467-024-49431-6

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