Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response

Franziska Walser; Monique P.C. Mulder; Benoît Bragantini; Sibylle Burger; Tatiana Gubser; Marco Gatti; Maria Victoria Botuyan; Alessandra Villa; Matthias Altmeyer; Dario Neri; Huib Ovaa; Georges Mer; Lorenza Penengo

doi:10.1016/j.molcel.2020.09.017

Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response

Franziska Walser, Monique P.C. Mulder, Benoît Bragantini, Sibylle Burger, Tatiana Gubser, Marco Gatti, Maria Victoria Botuyan, Alessandra Villa, Matthias Altmeyer, Dario Neri, Huib Ovaa, Georges Mer, Lorenza Penengo

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage. Mutating Thr12 prevents the removal of ubiquitin from H2AK15ub by USP51 deubiquitinating enzyme, leading to a pronounced accumulation of ubiquitinated chromatin. Chromatin modified by pUbT12 is inaccessible to 53BP1 but permissive to the homologous recombination (HR) proteins RNF169, RAD51, and the BRCA1/BARD1 complex. Phosphorylation of ubiquitin at Thr12 in the chromatin context is a new histone mark, H2AK15pUbT12, that regulates the DDR by hampering the activity of 53BP1 at damaged chromosomes.

Original language	English (US)
Pages (from-to)	423-436.e9
Journal	Molecular Cell
Volume	80
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2020.09.017
State	Published - Nov 5 2020

Keywords

53BP1
BRCA1/BARD1
DDR
DNA damage response
DNA repair
H2AK15pUbT12
RAD51
RNF168
RNF169
RNF8
USP51
chromatin ubiquitination
genome stability
histone mark H2AK15ub
pUbT12
phospho-ubiquitin Thr12
ubiquitin phosphorylation

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2020.09.017

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title = "Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response",

abstract = "The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage. Mutating Thr12 prevents the removal of ubiquitin from H2AK15ub by USP51 deubiquitinating enzyme, leading to a pronounced accumulation of ubiquitinated chromatin. Chromatin modified by pUbT12 is inaccessible to 53BP1 but permissive to the homologous recombination (HR) proteins RNF169, RAD51, and the BRCA1/BARD1 complex. Phosphorylation of ubiquitin at Thr12 in the chromatin context is a new histone mark, H2AK15pUbT12, that regulates the DDR by hampering the activity of 53BP1 at damaged chromosomes.",

keywords = "53BP1, BRCA1/BARD1, DDR, DNA damage response, DNA repair, H2AK15pUbT12, RAD51, RNF168, RNF169, RNF8, USP51, chromatin ubiquitination, genome stability, histone mark H2AK15ub, pUbT12, phospho-ubiquitin Thr12, ubiquitin phosphorylation",

author = "Franziska Walser and Mulder, {Monique P.C.} and Beno{\^i}t Bragantini and Sibylle Burger and Tatiana Gubser and Marco Gatti and Botuyan, {Maria Victoria} and Alessandra Villa and Matthias Altmeyer and Dario Neri and Huib Ovaa and Georges Mer and Lorenza Penengo",

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doi = "10.1016/j.molcel.2020.09.017",

language = "English (US)",

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T1 - Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response

AU - Walser, Franziska

AU - Mulder, Monique P.C.

AU - Bragantini, Benoît

AU - Burger, Sibylle

AU - Gubser, Tatiana

AU - Gatti, Marco

AU - Botuyan, Maria Victoria

AU - Villa, Alessandra

AU - Altmeyer, Matthias

AU - Neri, Dario

AU - Ovaa, Huib

AU - Mer, Georges

AU - Penengo, Lorenza

PY - 2020/11/5

Y1 - 2020/11/5

N2 - The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage. Mutating Thr12 prevents the removal of ubiquitin from H2AK15ub by USP51 deubiquitinating enzyme, leading to a pronounced accumulation of ubiquitinated chromatin. Chromatin modified by pUbT12 is inaccessible to 53BP1 but permissive to the homologous recombination (HR) proteins RNF169, RAD51, and the BRCA1/BARD1 complex. Phosphorylation of ubiquitin at Thr12 in the chromatin context is a new histone mark, H2AK15pUbT12, that regulates the DDR by hampering the activity of 53BP1 at damaged chromosomes.

AB - The ubiquitin system regulates the DNA damage response (DDR) by modifying histone H2A at Lys15 (H2AK15ub) and triggering downstream signaling events. Here, we find that phosphorylation of ubiquitin at Thr12 (pUbT12) controls the DDR by inhibiting the function of 53BP1, a key factor for DNA double-strand break repair by non-homologous end joining (NHEJ). Detectable as a chromatin modification on H2AK15ub, pUbT12 accumulates in nuclear foci and is increased upon DNA damage. Mutating Thr12 prevents the removal of ubiquitin from H2AK15ub by USP51 deubiquitinating enzyme, leading to a pronounced accumulation of ubiquitinated chromatin. Chromatin modified by pUbT12 is inaccessible to 53BP1 but permissive to the homologous recombination (HR) proteins RNF169, RAD51, and the BRCA1/BARD1 complex. Phosphorylation of ubiquitin at Thr12 in the chromatin context is a new histone mark, H2AK15pUbT12, that regulates the DDR by hampering the activity of 53BP1 at damaged chromosomes.

KW - 53BP1

KW - BRCA1/BARD1

KW - DDR

KW - DNA damage response

KW - DNA repair

KW - H2AK15pUbT12

KW - RAD51

KW - RNF168

KW - RNF169

KW - RNF8

KW - USP51

KW - chromatin ubiquitination

KW - genome stability

KW - histone mark H2AK15ub

KW - pUbT12

KW - phospho-ubiquitin Thr12

KW - ubiquitin phosphorylation

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DO - 10.1016/j.molcel.2020.09.017

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SN - 1097-2765

VL - 80

SP - 423-436.e9

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response

Abstract

Keywords

ASJC Scopus subject areas

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