RAD-ical New Insights into RAD51 Regulation

Abstract

The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.

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

“…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]. FOXP1 is a transcription factor essential for the development of major organs and known to be a tumor suppressor in prostrate and breast cancers [54,55].…”

High-content Imaging-based Pooled CRISPR Screens in Mammalian Cells

“…Six genes are involved in spindle function and chromosome segregation, which includes KIF11 26 , NUP62 27 , SPDL1 28 and three core chromosomal passenger complex (CPC) components INCENP, AURKB and CDCA8 29,30 . Three genes function in DNA damage and repair, namely TICRR 31,32 , TOP2A 33,34 and RAD51 35,36 , while the remaining four play roles in histone synthesis (CASP8AP2 37 ), DNA maintenance (DNA2 38,39 ) and cell cycle regulation (SKA1 40,41 and FBXO5 22,23 ) (Supplementary file 3). Some of these functions might directly explain the larger nuclei phenotype after knock down.…”

Analysis of Epigenetic Alterations in Homologous Recombination DNA Repair Genes in Male Breast Cancer

“…BRCA2, the most common high penetrance susceptibility gene for male BC, but also ATM, BRCA1, PALB2, RAD51, and RAD51 paralogs play important roles in HRR pathway [8]. RAD51 paralogs encode for proteins that structurally resemble RAD51 and congregate in vivo into three subcomplexes, comprising BCDX2 (RAD51B, RAD51C, RAD51D, XRCC2), CX3 (RAD51C, XRCC3), and the Shu complex (SWSAP1, SWS1) [7][8][9][10][11][12]. Indeed, the balance between BRCA2, RAD51 and RAD51 paralogs seems to be essential in HRR [8,12,13].…”

“…RAD51 paralogs encode for proteins that structurally resemble RAD51 and congregate in vivo into three subcomplexes, comprising BCDX2 (RAD51B, RAD51C, RAD51D, XRCC2), CX3 (RAD51C, XRCC3), and the Shu complex (SWSAP1, SWS1) [7][8][9][10][11][12]. Indeed, the balance between BRCA2, RAD51 and RAD51 paralogs seems to be essential in HRR [8,12,13]. Mutations in HRR genes, either somatic and/ or in the germline occur in multiple conditions, including hereditary breast and ovarian cancer susceptibility syndromes, in which there is also increased male BC risk [2,8,[14][15][16][17].…”