OB-Folds and Genome Maintenance: Targeting Protein–DNA Interactions for Cancer Therapy

SIMPLE SUMMARY: Genome replication, repair, recombination, and the DNA damage response (DDR) rely on a cadre of DNA binding proteins to execute and regulate these critical pathways. There are many structural motifs that support DNA-binding and included in these is the oligonucleotide/oligosaccharide binding fold (OB-fold). OB-folds are found across the tree of life and play critical roles in chromosome maintenance and stability. This paper reviews the current state of knowledge regarding structure, function, and involvement of OB-fold proteins in the DNA damage response, replication, and repair. We highlight a group of OB-fold DNA binding proteins and discuss how disruption of these critical protein–DNA interactions can be exploited in cancer therapy. ABSTRACT: Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a subset employ oligonucleotide/oligosaccharide binding folds (OB-fold) to facilitate the protein–DNA interactions. OB-fold motifs allow for sequence independent binding to single-stranded DNA (ssDNA) and can serve to position specific proteins at specific DNA structures and then, via protein–protein interaction motifs, assemble the machinery to catalyze the replication, repair, or recombination of DNA. This review provides an overview of the OB-fold structural organization of some of the most relevant OB-fold containing proteins for oncology and drug discovery. We discuss their individual roles in DNA metabolism, progress toward drugging these motifs and their utility as potential cancer therapeutics. While protein–DNA interactions were initially thought to be undruggable, recent reports of success with molecules targeting OB-fold containing proteins suggest otherwise. The potential for the development of agents targeting OB-folds is in its infancy, but if successful, would expand the opportunities to impinge on genome stability and maintenance pathways for more effective cancer treatment.