Plakophilins (Pkp-1, -2, and -3) comprise a family of armadillo repeat-containing proteins first identified as desmosomal plaque components, in which they link desmoplakin to the desmosomal cadherins. In addition to their role in desmosomal cell-cell adhesion, Pkps also localize to the nucleus, where they perform unknown functions. Of the three Pkps, Pkp-1 is most readily detected in the nucleus, where it is localized to the nucleoplasm. Pkp chimeras containing the Pkp-1 head domain and Pkp-3 armadillo repeat domain were localized to the nucleus in A431 cells, whereas Pkp chimeras containing the Pkp-3 head domain and Pkp-1 armadillo repeat domain localized to the desmosome and the cytosol. DNAse I digestion of chromatin in cultured cells results in loss of nuclear Pkp-1, suggesting that Pkp-1 associates specifically with nuclear components. In addition, in vitro assays revealed that the amino-terminal head domains of Pkps-1 and -2 were sufficient to bind single-stranded DNA. Induction of DNA damage induced a partial redistribution of Pkp-1 protein to the nucleolus, and depletion of Pkp-1 resulted in increased survival in response to DNA damage. These data suggest that in addition to mediating desmosome assembly, the nuclear pool of Pkp can influence cell survival by interactions with DNA.