Emerging Roles of RAD52 in Genome Maintenance

Abstract

The maintenance of genome integrity is critical for cell survival. Homologous recombination (HR) is considered the major error-free repair pathway in combatting endogenously generated double-stranded lesions in DNA. Nevertheless, a number of alternative repair pathways have been described as protectors of genome stability, especially in HR-deficient cells. One of the factors that appears to have a role in many of these pathways is human RAD52, a DNA repair protein that was previously considered to be dispensable due to a lack of an observable phenotype in knock-out mice. In later studies, RAD52 deficiency has been shown to be synthetically lethal with defects in BRCA genes, making RAD52 an attractive therapeutic target, particularly in the context of BRCA-deficient tumors.

Keywords: BRCA1; BRCA2; DNA repair; R-loops; RAD51; RAD52; RNA:DNA hybrids; double-strand break repair; genome instability; synthetic lethality.

Figure 1

Involvement of RAD52 in various pathways of genome maintenance: TC-HR (transcription-coupled homologous recombination), HR (homologous recombination), Processing of stalled forks (MUS81-dependent fork cleavage and protection against excessive fork reversal), BIR (break-induced replication), ALT (alternative lengthening of telomeres), TA-HRR (transcription-associated homologous recombination repair), MiDAS (mitotic DNA synthesis), Replication of UR-DNA (replication of under-replicated DNA in 53BP1 nuclear bodies), SSA (single-strand annealing), and RNA-templated repair. Pathways are categorized by the cell cycle phase in which they are predominately active [24,25,26,27,28,29,30].

Figure 2

RAD52 and RNA-containing substrates. (A) Affinity of human RAD52 for various nucleic acid substrates adapted from mobility shift assay reported in Welty et al., 2017 [52]. (B) Possible modes of RAD52 binding at R-loops (to ssDNA, ssRNA, or RNA:DNA hybrid structure). (C) RAD52 may facilitate R-loop formation at a double-strand break by either forward or inverse strand exchange.