Abstract
Homologous recombination (HR) repairs DNA double strand breaks (DSBs) and stabilizes replication forks (RFs). RAD51 is the recombinase for the HR pathway. To preserve genomic integrity, RAD51 forms a filament on the 3′ end of a DSB and on a single-stranded DNA (ssDNA) gap. But unregulated HR results in undesirable chromosomal rearrangements. This review describes the multiple mechanisms that regulate HR with a focus on those mechanisms that promote and contain RAD51 filaments to limit chromosomal rearrangements. If any of these pathways break down and HR becomes unregulated then disease, primarily cancer, can result.
Highlights
A cell might contain thousands of DNA lesions [1] that could potentially block DNA synthesis
RAD51 forms a filament on single-stranded DNA (ssDNA) to protect it from degradation by MRE11 and other nucleases, but it serves as the catalytic center for invasion and annealing to a homologous substrate usually provided by the sister chromatid
Deficient levels of BRCA2 and RAD51 allow MRE11 or DNA2 degradation to occur on the nascent strand that is dependent on replication fork remodelers SMARCAL1 (SWI/SNF-related matrixassociated actin-dependent regulator of chromatin subfamily A-like protein 1), ZRANB3 (Zinc Finger Ran-binding Domain-containing Protein 3) and HLTF [128,140]
Summary
A cell might contain thousands of DNA lesions [1] that could potentially block DNA synthesis. RAD51 is loaded onto ssDNA in a gap or at the 3’ end of a DSB. This process can remodel and remove toxic filaments. DSB repair involves the invading strand stabilizing a D-loop structure by capturing the complementary strand on the other DSB end to form of a double Holliday Junction (dHJ). RAD51 initiates HR by forming a filament on ssDNA via a self-interaction [9] that serves as the catalytic center for a homology search in the duplex and joint formation between homologous substrates (Figure 1). BRCA1 enables HR through 5’ to 3’ resection of DSBs to generate 3’ ssDNA overhangs that provide a substrate for RAD51 binding and by loading RAD51 onto the ssDNA [15].
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