And-1 coordinates with polymerase δ to regulate nucleotide excision repair and UVB-induced skin tumorigenesis.

Abstract

The nucleotide excision repair (NER) pathway is the primary mechanism for removing UVB-induced photoproducts in mammals. While early steps of NER are well defined, the later step of gap-filling DNA synthesis remains incompletely understood. Here, we report And-1, a DNA replication and repair factor, as a critical regulator of this process. And-1 localizes to UV lesions, directly interacts with the catalytic subunit of DNA polymerase δ (p125), and promotes its recruitment to facilitate repair synthesis. In vitro, And-1 enhances p125 polymerase activity. Importantly, And-1 function in NER requires phosphorylation at T826, which strengthens its binding to both damaged DNA and p125. To evaluate its physiological relevance, we generated phosphorylation-deficient And-1 knock-in mice. These mice exhibited impaired NER and developed keratoacanthomas upon chronic UVB exposure. Collectively, our findings uncover And-1 as a pivotal factor in NER-mediated DNA repair and highlight its role in skin tumorigenesis.