RAD51BActivity and Cell Cycle Regulation in Response to DNA Damage in Breast Cancer Cell Lines

Abstract

Common genetic variants mapping to two distinct regions of RAD51B, a paralog of RAD51, have been associated with breast cancer risk in genome-wide association studies (GWAS). RAD51B is a plausible candidate gene because of its established role in the homologous recombination (HR) process. How germline genetic variation in RAD51B confers susceptibility to breast cancer is not well understood. Here, we investigate the molecular function of RAD51B in breast cancer cell lines by knocking down RAD51B expression by small interfering RNA and treating cells with DNA-damaging agents, namely cisplatin, hydroxyurea, or methyl-methanesulfonate. Our results show that RAD51B-depleted breast cancer cells have increased sensitivity to DNA damage, reduced efficiency of HR, and altered cell cycle checkpoint responses. The influence of RAD51B on the cell cycle checkpoint is independent of its role in HR and further studies are required to determine whether these functions can explain the RAD51B breast cancer susceptibility alleles.

Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma

“… 39 RAD51B , one member of the human RAD51 (MIM: 179617 ) paralogs, plays a central role in homologous DNA recombination. 40 Increased RAD51B protein level has been reported in various cancers, especially gynecological tumors, and linked to uncontrolled recombination, genome instability, tumor recurrence and progression, and increased resistance of tumors to radiotherapy and chemotherapy. 40 Interestingly, translocation of RAD51B with other genes has been reported, for example, HMGA2-RAD51B in uterine leiomyoma.…”

“… 40 Increased RAD51B protein level has been reported in various cancers, especially gynecological tumors, and linked to uncontrolled recombination, genome instability, tumor recurrence and progression, and increased resistance of tumors to radiotherapy and chemotherapy. 40 Interestingly, translocation of RAD51B with other genes has been reported, for example, HMGA2-RAD51B in uterine leiomyoma. 41 However, to the best of our knowledge, the EIF3E-RAD51B translocation has not been previously reported in human cancer.…”

Phosphorylation of STAT1 serine 727 enhances platinum resistance in uterine serous carcinoma

“…There are many factors that modulate the efficacy of cisplatin therapy such as DNA repair, drug uptake and efflux and drug inactivation . To identify the factors involved in platinum resistance, Mock and shSTAT1 cells treated with cisplatin were used to assess DNA repair pathways such as the homologous recombination (HR) pathway, nonhomologous end joining (NHEJ) pathway, FANCD2 crosslink pathway, mismatch pathway, and nucleotide excision repair (NER) pathway . For the HR pathway, nuclear Rad51 foci in Mock and shSTAT1 cells were assessed with or without 1 μM cisplatin treatment for 24 hr by immunostaining and western blotting.…”

“…Resistance to cisplatin is based on several mechanisms such as decreased DNA damage, enhanced DNA repair, reduced cellular accumulation of platinum and platinum inactivation. Among these, HR is a key pathway in DNA repair for variety of cancers; moreover, nuclear Rad51 foci formation is a hallmark of the HR DNA repair pathway . NNHEJ and FANCD2 crosslinking also play important roles in regulating the signal from BRCA1 and Rad51 to induce downstream repair pathways .…”

Loss of TRP53 (p53) accelerates tumorigenesis and changes the tumor spectrum of SJL/J mice

“…A specific example is that mutations in p53 amplify EGFR family signaling to promote mammary tumorigenesis [46]. RAD51B is a homologous recombination DNA repair protein that interacts with TRP53 [49,50], and its activity influences cell cycle checkpoint control, independent of its role in homologous recombination in breast cancer [51]. It is also known that RAD51B, being a homologous recombination protein, shares its function to maintain genome stability with TRP53 [52,53].…”