Ubiquitin Phosphorylation at Thr12 Modulates the DNA Damage Response

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-st...

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Bibliographic Details
Published in:Molecular cell Vol. 80; no. 3; p. 423
Main Authors: Walser, Franziska, Mulder, Monique P C, Bragantini, Benoît, Burger, Sibylle, Gubser, Tatiana, Gatti, Marco, Botuyan, Maria Victoria, Villa, Alessandra, Altmeyer, Matthias, Neri, Dario, Ovaa, Huib, Mer, Georges, Penengo, Lorenza
Format: Journal Article
Language:English
Published: United States 05.11.2020
Subjects:
Animals
Cell Line
Cell Line, Tumor
Chromatin - metabolism
DNA - metabolism
DNA Breaks, Double-Stranded
DNA Damage - genetics
DNA Damage - physiology
DNA End-Joining Repair - genetics
DNA Repair - genetics
DNA-Binding Proteins - metabolism
Histones - metabolism
Homologous Recombination - physiology
Humans
Intracellular Signaling Peptides and Proteins - metabolism
Nuclear Proteins - metabolism
Phosphorylation
Signal Transduction - genetics
Threonine - metabolism
Tumor Suppressor p53-Binding Protein 1 - metabolism
Tumor Suppressor p53-Binding Protein 1 - physiology
Ubiquitin - genetics
Ubiquitin - metabolism
Ubiquitin-Protein Ligases - metabolism
Ubiquitination
H2AK15pUbT12
genome stability
pUbT12
BRCA1/BARD1
DNA damage response
phospho-ubiquitin Thr12
53BP1
RNF8
chromatin ubiquitination
DNA repair
RNF168
DDR
RAD51
RNF169
histone mark H2AK15ub
ubiquitin phosphorylation
USP51
ISSN:1097-4164, 1097-4164
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Summary: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.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2020.09.017