Abstract
Loss of genome stability is one of the hallmarks of the enabling characteristics of cancer development. Homologous recombination is a DNA repair process that often breaks down as a prelude to developing cancer. Conversely, homologous recombination can be the Achilles' heel in common anti-cancer therapies, which are effective by inducing irreparable DNA damage. Here, we review recent structural and functional studies of RAD51, the protein that catalyzes the defining step of homologous recombination: homology recognition and DNA strand exchange. Specific mutations can be linked to structural changes and known essential functions. Additional RAD51 interactions and functions may be revealed. The identification of viable mutations in this essential protein may help define the range of activity and interactions needed. All of this information provides opportunities to fine-tune existing therapies based on homologous recombination status, guide diagnosis, and hopefully develop new clinical tools.
Highlights
Homologous recombination (HR) is essential for the maintenance of genome stability
By taking advantage of DNA sequence complementarity, HR is uniquely suited to repair a variety of DNA lesions—such as DNA double-strand breaks (DSBs) and stalled or collapsed DNA replication forks—that affect both strands of the double helix[1]
Initial nucleation of RAD51 on the singlestranded DNA (ssDNA) is followed by binding of additional protomers, resulting in a dynamic nucleoprotein filament with homology search and DNA strand exchange capabilities[2]
Summary
Homologous recombination (HR) is essential for the maintenance of genome stability. By taking advantage of DNA sequence complementarity, HR is uniquely suited to repair a variety of DNA lesions—such as DNA double-strand breaks (DSBs) and stalled or collapsed DNA replication forks—that affect both strands of the double helix[1]. More detailed structural information is available on the interface between monomers, which comprises the ATPase active site of DNA-bound recombinases[8] Additional dynamic properties such as kinetic parameters for filament assembly and disassembly as well as continuity and flexibility have more recently been defined on the basis of single-molecule methods[9]. The enhanced activity is coupled to weaker DNA binding and formation of less stable/more dynamic filaments, emphasizing the essential role of dynamic interactions among RAD51 itself and DNA to perform its core biochemical function[18] Another example illustrating the importance of the RAD51–RAD51 interface is demonstrated by using small-molecule chemical inhibitor RI-119. RAD51 mutations associated with human disease Because RAD51 nucleoprotein filament formation and dynamics are essential elements of its DNA strand exchange function, small changes to the protomers could cause dramatic effects. Mutation Sort of DNA-binding ATPase activity Strand exchange Reference(s) mutation activity activity
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