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

Abstract

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.

Evaluation of stromal cell infiltration in the tumor microenvironment enable prediction of treatment sensitivity and prognosis in colon cancer

“…To address the role of GPX3 in mediating chemoresistance in colon cancer cells, several in vitro and in vivo experiments, including cell culture, cell transfection, Methylthiazolyl-tetrazolium (MTT) assay, clonogenic assay, western blotting, real-time quantitative reverse-transcription polymerase chain reaction, immunohistochemistry staining, and subcutaneous tumor formation assays, were performed as previously described [12] .…”

Prognostic Significance and Immunological Role of FBXO5 in Human Cancers: A Systematic Pan-Cancer Analysis

“…Notably, highly expressed FBXO5 in STAD (stomach adenocarcinoma) was a protective factor for DFI and PFI survival, and this was different from most cancers in which increased FBXO5 acted as an unfavorable prognostic factor, implying that FBXO5 may have specific functions in STAD. A previous study on the role of CRIP1 can well explain the protective role of FBXO5 in gastric cancer (27). Simply put, CRIP1 is overexpressed in gastric cancer and CRIP1 deficiency inhibits the process of homologous recombination and increases susceptibility to chemotherapy in gastric cancer cells.…”

Comprehensive Analysis of CRIP1 Expression in Acute Myeloid Leukemia

“…The role of CRIP1 expression in AML patients has been rarely reported and is largely unknown. In fact, CRIP1 was reported to have tumor-specific oncogenic or tumor-suppressive properties (Sun et al, 2021). In colorectal cancer, CRIP1 could facilitate the 5-FU drug resistance by downregulating the Fas and Fasmediated apoptosis-related proteins' expression (Zhang et al, 2019).…”

“…Among the markers of the CD34 + CD117 dim cells, cysteinerich intestinal protein (CRIP1) belongs to the LIM/double-zinc finger protein family and is abnormally expressed in a variety of tumors, including breast cancer, colorectal tumors, and thyroid cancer (Ludyga et al, 2013;Li et al, 2017;He et al, 2019;Zhang et al, 2019). CRIP1 may have tumor-type-specific oncogenic or tumor-suppressive properties (Sun et al, 2021). In detail, using the RNA-seq data from the Cancer Genome Atlas (TCGA) AML project, we discovered that CRIP1 was highly expressed in AML patients, including the M0-M7 subtypes (Li et al, 2021).…”