Arnold Moriah R, Cohn Gabriel M, Oxe Kezia Catharina, Elliott Somarr N, Moore Cynthia, Zhou Allison May, Laraia Peter V, Shekoohi Sahar, Brownell Dillon, Sears Rosalie C, Woltjer Randall L, Meshul Charles K, Witt Stephan N, Larsen Dorthe H, Unni Vivek K
Medical Scientist Training Program, Oregon Health and Science University, Portland, OR, USA.
Department of Neurology and Jungers Center for Neurosciences Research, Oregon Health and Science University, Portland, OR, USA.
Sci Adv. 2025 Apr 11;11(15):eadq2519. doi: 10.1126/sciadv.adq2519. Epub 2025 Apr 9.
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.
尽管多项研究表明帕金森病（PD）患者患皮肤癌黑色素瘤的风险增加，但其相关机制仍知之甚少，但黑色素瘤细胞中与PD相关的蛋白质α-突触核蛋白（αSyn）表达增加可能很重要。我们之前的研究表明，αSyn可以促进DNA双链断裂（DSB）修复，提高基因组稳定性。我们现在发现，αSyn在黑色素瘤的核仁中优先富集，在那里它与DNA损伤标记物和DSB共定位。在核仁核糖体DNA（rDNA）中特异性诱导DSB会增加损伤部位附近的αSyn水平。αSyn基因敲除会增加基线时、特定rDNA DSB诱导后核仁内的DNA损伤，并延长从这种诱导损伤中恢复的速度。αSyn在共济失调毛细血管扩张突变信号传导的下游很重要，可促进MDC1介导的53BP1募集到DSB，减少微核形成，并促进细胞增殖、迁移和侵袭。
