CRIP1 cooperates with BRCA2 to drive the nuclear enrichment of RAD51 and to facilitate homologous repair upon DNA damage induced by chemotherapy

Autor: Yannan Zheng, Min Shi, Zhenhua Huang, Jianping Bin, Huiying Sun, Jianhua Wu, Rui Zhou, Dongqiang Zeng, Xiaoxiang Rong, Na Huang, Li Sun, Dingling Zhang, Zhaowei Wen, Yulin Liao, Wangjun Liao
Rok vydání: 2021
Předmět:
Zdroj: Oncogene
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-021-01932-0
Popis: Homologous recombination (HR) repair is an important determinant of chemosensitivity. However, the mechanisms underlying HR regulation remain largely unknown. Cysteine-rich intestinal protein 1 (CRIP1) is a member of the LIM/double-zinc finger protein family and is overexpressed and associated with prognosis in several tumor types. However, to date, the functional role of CRIP1 in cancer biology is poorly understood. Here we found that CRIP1 downregulation causes HR repair deficiency with concomitant increase in cell sensitivity to cisplatin, epirubicin, and the poly ADP-ribose polymerase (PARP) inhibitor olaparib in gastric cancer cells. Mechanistically, upon DNA damage, CRIP1 is deubiquitinated and upregulated by activated AKT signaling. CRIP1, in turn, promotes nuclear enrichment of RAD51, which is a prerequisite step for HR commencement, by stabilizing BRCA2 to counteract FBXO5-targeted RAD51 degradation and by binding to the core domain of RAD51 (RAD51184–257) in coordination with BRCA2, to facilitate nuclear export signal masking interactions between BRCA2 and RAD51. Moreover, through mass spectrometry screening, we found that KPNA4 is at least one of the carriers controlling the nucleo-cytoplasmic distribution of the CRIP1–BRCA2–RAD51 complex in response to chemotherapy. Consistent with these findings, RAD51 inhibitors block the CRIP1-mediated HR process, thereby restoring chemotherapy sensitivity of gastric cancer cells with high CRIP1 expression. Analysis of patient specimens revealed an abnormally high level of CRIP1 expression in GC tissues compared to that in the adjacent normal mucosa and a significant negative association between CRIP1 expression and survival time in patient cohorts with different types of solid tumors undergoing genotoxic treatments. In conclusion, our study suggests an essential function of CRIP1 in promoting HR repair and facilitating gastric cancer cell adaptation to genotoxic therapy.
Databáze: OpenAIRE
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