Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
Menée à l'aide de lignées cellulaires et d'échantillons biopsiques de mélanomes, cette étude met en évidence un mécanisme par lequel l'alpha-synucléine, une protéine associée à la neurodégénérescence, favorise la prolifération, la migration et le processus invasif des cellules cancéreuses en régulant positivement la réparation des cassures double-brin de l'ADN nucléaire
Although an increased risk of the skin cancer melanoma in people with Parkinson’s disease (PD) has been shown in multiple studies, the mechanisms involved are poorly understood, but increased expression of the PD-associated protein alpha-synuclein (αSyn) in melanoma cells may be important. Our previous work suggests that αSyn can facilitate DNA double-strand break (DSB) repair, promoting genomic stability. We now show that αSyn is preferentially enriched within the nucleolus in melanoma, where it colocalizes with DNA damage markers and DSBs. Inducing DSBs specifically within nucleolar ribosomal DNA (rDNA) increases αSyn levels near sites of damage. αSyn knockout increases DNA damage within the nucleolus at baseline, after specific rDNA DSB induction, and prolongs the rate of recovery from this induced damage. αSyn is important downstream of ataxia-telangiectasia–mutated signaling to facilitate MDC1-mediated 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion. Alpha-synuclein, a neurodegeneration-associated protein, functions in nucleolar DNA double-strand break repair in melanoma.
Science Advances , article en libre accès 2024