Abstract
Rad52 in yeast is a key player in homologous recombination (HR), but mammalian RAD52 is dispensable for HR as shown by the lack of a strong HR phenotype in RAD52-deficient cells and in RAD52 knockout mice. RAD52 function in mammalian cells first emerged with the discovery of its important backup role to BRCA (breast cancer genes) in HR. Recent new evidence further demonstrates that RAD52 possesses multiple activities to cope with replication stress. For example, replication stress-induced DNA repair synthesis in mitosis (MiDAS) and oncogene overexpression-induced DNA replication are dependent on RAD52. RAD52 becomes essential in HR to repair DSBs containing secondary structures, which often arise at collapsed replication forks. RAD52 is also implicated in break-induced replication (BIR) and is found to inhibit excessive fork reversal at stalled replication forks. These various functions of RAD52 to deal with replication stress have been linked to the protection of genome stability at common fragile sites, which are often associated with the DNA breakpoints in cancer. Therefore, RAD52 has important recombination roles under special stress conditions in mammalian cells, and presents as a promising anti-cancer therapy target.
Highlights
Genome instability is a hallmark of cancer, and gross chromosomal rearrangements (GCR) are frequently found in the cancer genome [1,2]
We further showed that double-strand breaks (DSBs) caused by fork stalling at common fragile sitessites (CFSs)-ATs are repaired by homologous recombination (HR) which is dependent on RAD52 [26]
The role of RAD52 in mammalian cells has been puzzling for years due to the viability of RAD52 knock-out mice and the lack of strong DNA repair phenotype in RAD52-deficient cells
Summary
Genome instability is a hallmark of cancer, and gross chromosomal rearrangements (GCR) are frequently found in the cancer genome [1,2]. Homologous recombination (HR) emerges as a critical DSB repair pathway in mammalian cells [4]. The 3’ end of the invading strand is used as a primer for new DNA synthesis. GC occurs mainly by synthesis-dependent strand annealing (SDSA) in mitotic cells, during which the other resected end anneals to the newly synthesized strand that has been displaced from its template. When only one DSB end has homology to the donor template, break-induced replication (BIR) is used (Figure 1B, [8,9,10,11]). In In contrast to to GC, DNA synthesis in in BIR often continues over and contrast synthesis often continues over a long distance and can proceed to the end of a chromosome in yeast [14,15,16].
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