Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma

Abstract

Although an increased risk of the skin cancer melanoma in people with Parkinsons Disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (Syn) in melanoma cells may be important. Our previous work suggests that Syn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that Syn is preferentially enriched within the nucleolus in the SK-MEL28 melanoma cell line, where it colocalizes with DNA damage markers and DSBs. Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases Syn levels near sites of damage. Syn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage. Syn is important downstream of ATM signaling to facilitate 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.