Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
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.
Authors
- Cindy Moore (ORCID: https://orcid.org/0000-0002-9852-8748)
- Kezia Catharina Oxe (ORCID: https://orcid.org/0000-0002-4921-4750)
- Charles K. Meshul (ORCID: https://orcid.org/0000-0002-3908-0795)
- Allison May Zhou (ORCID: https://orcid.org/0009-0007-9658-3886)
- Dorthe Helena Larsen (ORCID: https://orcid.org/0000-0002-8280-1252)
- Sahar Shekoohi (ORCID: https://orcid.org/0009-0007-4545-4523)
- Moriah R. Arnold (ORCID: https://orcid.org/0000-0002-5916-7978)
- Stephan N. Witt (ORCID: https://orcid.org/0000-0002-6462-2840)
- Gabriel M. Cohn (ORCID: https://orcid.org/0000-0001-5901-2506)
- Rosalie C. Sears (ORCID: https://orcid.org/0000-0003-1558-2413)
- Vivek K. Unni (ORCID: https://orcid.org/0000-0001-8833-6542)
- R. L. Woltjer (ORCID: https://orcid.org/0000-0003-0755-9846)
- Peter V. Laraia (ORCID: https://orcid.org/0009-0002-4411-9831)
- Dillon Brownell (ORCID: https://orcid.org/0009-0005-2432-1460)
- Somarr N. Elliott (ORCID: https://orcid.org/0009-0002-4347-9923)
Institutions
- College of San Mateo (US)
- Oregon Health & Science University (US)
- Veterans Health Administration (US)
- Center for Neurosciences (US)
- Danish Cancer Society (DK)
- Louisiana State University Health Sciences Center Shreveport (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1126/sciadv.adq2519
- Citations
- 5
- Primary Topic
- DNA Repair Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 4.03