TY - JOUR
T1 - Fine-Tuning of DNA Damage-Dependent Ubiquitination by OTUB2 Supports the DNA Repair Pathway Choice
AU - Kato, Kiyoko
AU - Nakajima, Kazuhiro
AU - Ui, Ayako
AU - Muto-Terao, Yuri
AU - Ogiwara, Hideaki
AU - Nakada, Shinichiro
N1 - Funding Information:
We are grateful to J. Kobayashi, A. Kato, K. Komatsu, Y. Sato, and S. Fukai for reagents and technical support. We thank D. Durocher, A. Shibata, R. Sakasai, and S. Takeda for the critical reading of this manuscript. This work was supported by MEXT KAKENHI Grant (25131708 and 22131006), JSPS KAKENHI Grant (23310040), Health and Labour Sciences Research Grant, the Takeda Science Foundation, and the Uehara Memorial Foundation. A part of this work was carried out under the Cooperative Research Project Program of the Institute of Development, Aging and Cancer at Tohoku University.
PY - 2014/2/20
Y1 - 2014/2/20
N2 - DNA double-strand breaks (DSBs) are deleterious lesions that lead to genetic mutations and cell death. Protein ubiquitination mediated by the E3 ubiquitin ligase RNF8 within the regions surrounding DSBs recruits DNA DSB response (DDR) factors and induces chromatin remodeling, which supports cell survival after DNA damage. Nevertheless, the impact of RNF8-mediated ubiquitination on DNA repair remains to be elucidated. Here, we report that depletion of the deubiquitinating enzyme OTUB2 enhances RNF8-mediated ubiquitination in an early phase of the DDR and promotes faster DSB repair but suppresses homologous recombination. The rapid ubiquitination results in accelerated accumulation of 53BP1 and RAP80 at DSBs, whichin turn protects DSB ends from resection in OTUB2-depleted cells. Mechanistically, OTUB2 suppresses RNF8-mediated L3MBTL1 ubiquitination and Lys 63-linked ubiquitin chain formation in a deubiquitinating activity-dependent manner. Thus, OTUB2 fine-tunes the speed of DSB-induced ubiquitination so that the appropriate DNA repair pathway is chosen.
AB - DNA double-strand breaks (DSBs) are deleterious lesions that lead to genetic mutations and cell death. Protein ubiquitination mediated by the E3 ubiquitin ligase RNF8 within the regions surrounding DSBs recruits DNA DSB response (DDR) factors and induces chromatin remodeling, which supports cell survival after DNA damage. Nevertheless, the impact of RNF8-mediated ubiquitination on DNA repair remains to be elucidated. Here, we report that depletion of the deubiquitinating enzyme OTUB2 enhances RNF8-mediated ubiquitination in an early phase of the DDR and promotes faster DSB repair but suppresses homologous recombination. The rapid ubiquitination results in accelerated accumulation of 53BP1 and RAP80 at DSBs, whichin turn protects DSB ends from resection in OTUB2-depleted cells. Mechanistically, OTUB2 suppresses RNF8-mediated L3MBTL1 ubiquitination and Lys 63-linked ubiquitin chain formation in a deubiquitinating activity-dependent manner. Thus, OTUB2 fine-tunes the speed of DSB-induced ubiquitination so that the appropriate DNA repair pathway is chosen.
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U2 - 10.1016/j.molcel.2014.01.030
DO - 10.1016/j.molcel.2014.01.030
M3 - Article
C2 - 24560272
AN - SCOPUS:84894067659
SN - 1097-2765
VL - 53
SP - 617
EP - 630
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -