NUCKS1 is a novel RAD51AP1 paralog important for homologous recombination and genome stability

NUCKS1 (nuclear casein kinase and cyclindependentkinase substrate 1) is a 27 kD chromosomal,vertebrate-specific protein, for which limitedfunctional data exist. Here, we demonstrate thatNUCKS1 shares extensive sequence homology withRAD51AP1 (RAD51 associated protein 1), suggestingthat these two proteins are paralogs. Similar tothe phenotypic effects of RAD51AP1 knockdown, wefind that depletion of NUCKS1 in human cells impairsDNA repair by homologous recombination (HR) andchromosome stability. Depletion of NUCKS1 also resultsin greatly increased cellular sensitivity to mitomycinC (MMC), and in increased levels of spontaneousand MMC-induced chromatid breaks. NUCKS1is critical to maintaining wild type HR capacity, and,as observed for a number of proteins involved inthe HR pathway, functional loss of NUCKS1 leadsto a slow down in DNA replication fork progressionwith a concomitant increase in the utilizationof new replication origins. Interestingly, recombinantNUCKS1 shares the same DNA binding preferenceas RAD51AP1, but binds to DNA with reduced affinitywhen compared to RAD51AP1. Our results showthat NUCKS1 is a chromatin-associated protein witha role in the DNA damage response and in HR, a DNArepair pathway critical for tumor suppression.