In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3860-3860
Abstract:
In DNA damage response (DDR), histone ubiquitination by RNF168 is a critical event, which orchestrates the recruitment of downstream DDR factors, e.g. BRCA1 and 53BP1. Here, we report USP7 deubiquitinase regulates the stability of RNF168. We showed that USP7 disruption impairs the monoubiquitination of H2A (uH2A) and ultraviolet radiation (UVR)-induced monoubiquitination of γH2AX, and decreases the levels of pBmi1, Bmi1, RNF168, pChk1 and BRCA1. USP7 silencing by siRNA reduces uH2A and UVR-induced monoubiquititination of γH2AX, as well as the levels of Ring1B, Bmi1, RNF168 and BRCA1, recapitulating the chronic USP7 deficiency. USP7 disruption also compromises the formation of UVR-induced foci (UVRIF) and ionizing radiation-induced foci (IRIF) of uH2A, poly-K63-ubiquititination and BRCA1, but does not affect UVRIF and IRIF of 53BP1. USP7 was shown to physically bind RNF168 in vitro and in vivo. Overexpression of wild-type USP7, but not its catalytic-inactive or interaction-defective mutants, prevents UVR-induced RNF168 degradation. Both USP7 mutants are unable to cleave Ub-conjugates of RNF168 in vivo. Furthermore, ectopic expression of RNF168, or both RNF8 and RNF168 together, rescue the formation of UVRIF and IRIF of poly-K63-ubiquititination and BRCA1. Taken together, these findings reveal an important role of USP7 in regulating ubiquitin-dependent signaling via stabilization of RNF168. Note: This abstract was not presented at the meeting. Citation Format: Qianzheng Zhu, Nidhi Sharma, Jingshan He, Gulzar Wani, Altaf A. Wani. USP7 deubiquitinase promotes ubiquitin-dependent DNA damage signaling by stabilizing RNF168. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3860. doi:10.1158/1538-7445.AM2015-3860
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2015-3860
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2015
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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