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.
Highlights
Introduction to DoubleStrand Break and RepairExogenous and endogenous DNA damage is constantly challenging our genomic integrity.Exogenous DNA damaging agents, such as radiation, ultraviolet light, and chemicals, or endogenously generated DNA damage, such as errors in replication or cellular processes that generate reactive oxygen species, create a wide variety of DNA lesions [1]
Accurate DNA repair is a key part of the DNA damage response (DDR), and its loss leads to genome instability, which is a hallmark of cancer development [4]
RAD51 filament formation is a central step in homologous recombination (HR) and is highly conserved throughout eukaryotes
Summary
Exogenous and endogenous DNA damage is constantly challenging our genomic integrity. Exogenous DNA damaging agents, such as radiation, ultraviolet light, and chemicals, or endogenously generated DNA damage, such as errors in replication or cellular processes that generate reactive oxygen species, create a wide variety of DNA lesions [1]. HR is a tightly regulated and faithful template-guided repair process that replaces the lost or resected DNA around the damage using the information provided by an intact homologous sequence such as a sister chromatid or homologous chromosome This increased fidelity ensures the preservation of the genome through each cell division. Extensive resection can result in loss of heterozygosity by alternative deleterious repair pathways such as single-strand annealing (SSA; Figure 1B) or break-induced replication (BIR; not pictured) [18]. During synthesis-dependent strand annealing (SDSA), only one-end invasion occurs, forming a single Holliday junction, and this intermediate is dissolved into an NCO product (Figure 1F) [22]. Much of what we know about the homology search is based upon work done in model organisms such as yeast
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