Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks

Dong Hyun Lee, Sanket S. Acharya, Mijung Kwon, Pascal Drane, Yinghua Guan, Guillaume Adelmant, Peter Kalev, Jagesh Shah, David Pellman, Jarrod A. Marto, Dipanjan Chowdhury

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

Excluding 53BP1 from chromatin is required to attenuate the DNA damage response during mitosis, yet the functional relevance and regulation of this exclusion are unclear. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif. Phosphorylating these sites blocks the interaction of the UDR motif with mononuclesomes containing ubiquitinated histone H2A and impedes binding of 53BP1 to mitotic chromatin. Ectopic recruitment of 53BP1-T1609A/S1618A to mitotic DNA lesions was associated with significant mitotic defects that could bereversed by inhibiting nonhomologous end-joining. We also reveal that protein phosphatase complex PP4C/R3β dephosphorylates T1609 and S1618 toallow the recruitment of 53BP1 to chromatin in G1 phase. Our results identify key sites of 53BP1 phosphorylation during mitosis, identify the counteracting phosphatase complex that restores the potential for DDR during interphase, and establish the physiological importance of this regulation.

Original languageEnglish
Pages (from-to)512-525
Number of pages14
JournalMolecular Cell
Volume54
Issue number3
DOIs
StatePublished - 8 May 2014

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