RAD51 Gene Family Structure and Function

Abstract

Accurate DNA repair and replication are critical for genomic stability and cancer prevention. RAD51 and its gene family are key regulators of DNA fidelity through diverse roles in double-strand break repair, replication stress, and meiosis. RAD51 is an ATPase that forms a nucleoprotein filament on single-stranded DNA. RAD51 has the function of finding and invading homologous DNA sequences to enable accurate and timely DNA repair. Its paralogs, which arose from ancient gene duplications of RAD51, have evolved to regulate and promote RAD51 function. Underscoring its importance, misregulation of RAD51, and its paralogs, is associated with diseases such as cancer and Fanconi anemia. In this review, we focus on mammalian RAD51 structure and function and highlight the use of model systems to enable mechanistic understanding of RAD51 cellular roles. We also discuss how misregulation of the RAD51 gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51. Expected final online publication date for the Annual Review of Genetics, Volume 54 is November 23, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Kinase CDK2 in Mammalian Meiotic Prophase I: Screening for Hetero- and Homomorphic Sex Chromosomes

“…Analysis of the behavior of the meiotic chromosomes in prophase I was carried out using the immunocytochemical study of synaptonemal complexes (SC), the multi-protein structures that facilitate synapsis of homologous chromosomes [ 22 ]. In addition to CDK2 antibodies to identify this kinase, we used antibodies to proteins RAD51 and MLH1 (a mismatch repair protein) as markers for DNA double-strand breaks and recombination [ 23 , 24 ]. We studied seven rodent species from four subfamilies and three families with various sex chromosome systems, reflecting different evolutionary stages ( Table S1 , Figure S1 ): The Norwegian rat Rattus norvegicus (Muridae), with XX-XY and PAR, the common vole Microtus arvalis with XX, achiasmatic XY and no PAR; the lesser mole rat Nannospalax leucodon (Spalacidae), with XX-XY and PAR; the gray dwarf hamster Cricetulus migratorius (Cricetidae), with XX-XY, PAR and equal-length heteromorphic chromosomes; and three species with isomorphic (homomorphic) sex chromosomes for both sexes: The northern mole vole Ellobius talpinus , the eastern mole vole E. tancrei , and the Alay mole vole Ellobius alaicus (male XX with broad central asynaptic zone [ 25 , 26 ] and female XX with delayed synapsis [ 27 ]).…”

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma

“…One of the most robust markers of defective HR in cancer is elevated mRNA expression of RAD51, an ATPase central to HR repair (13)(14)(15)(16). At sites of stalled DNA replication, RAD51 protects single-strand DNA and facilitates recruitment of BRCA1/2 (7,8,17). Additionally, RAD51, and its homologs, directly participate in HR repair by facilitating strand-invasion of homologous DNA sequences.…”

Rad51 paralog complex Rad55–Rad57 acts as a molecular chaperone during homologous recombination

“…Importantly, RPA inhibits Rad51– ssDNA filament assembly due to the high affinity of RPA for ssDNA. This inhibitory effect must be overcome with the help of positive HR regulators called “mediators” that stimulate Rad51 filament assembly on RPA–ssDNA (Bonilla et al, 2020; Kowalczykowski, 2015; Mehta and Haber, 2014; Prakash et al, 2015; San Filippo et al, 2008). Rad51 paralogs are classified as HR mediators and they are broadly conserved across eukaryotes, however, the mechanistic basis for Rad51 paralog function remains poorly defined (Bonilla et al, 2020; Prakash et al, 2015; Sullivan and Bernstein, 2018).…”

“…This inhibitory effect must be overcome with the help of positive HR regulators called “mediators” that stimulate Rad51 filament assembly on RPA–ssDNA (Bonilla et al, 2020; Kowalczykowski, 2015; Mehta and Haber, 2014; Prakash et al, 2015; San Filippo et al, 2008). Rad51 paralogs are classified as HR mediators and they are broadly conserved across eukaryotes, however, the mechanistic basis for Rad51 paralog function remains poorly defined (Bonilla et al, 2020; Prakash et al, 2015; Sullivan and Bernstein, 2018). Rad51 paralogs share ~20% identity to the conserved central ATPase core domain of Rad51, with little to no similarity outside this region (Bonilla et al, 2020; Prakash et al, 2015; Sullivan and Bernstein, 2018).…”