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 the SK-MEL28 melanoma cell line, 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 ATM signaling to facilitate 53BP1 recruitment to DSBs, reducing micronuclei formation and promoting cellular proliferation, migration, and invasion.

Treacle is Upregulated in Cancer and Correlates With Poor Prognosis.

Treacle/TCOF1 is an adaptor protein specifically associated with nucleolar chromatin. In the nucleolus it stimulates ribosome biogenesis, thereby promoting growth and proliferation. A second role of Treacle has emerged as a coordinator of the nucleolar responses to DNA damage, where it facilitates nucleolar DNA repair and cellular survival after genotoxic insults. The involvement of Treacle in multiple fundamental processes such as growth, proliferation, and genome stability, which are tightly linked to cancer, raises the question of Treacle's role in the development of this disease. On one hand, overexpression of Treacle could stimulate nucleolar transcription and ribosome biogenesis providing a growth advantage in cancer cells. On the other hand, the function of Treacle as a gatekeeper in response to nucleolar DNA damage could favor mutations that would impair its function. In this perspective, we analyze paired Treacle expression data from the Cancer Genome Atlas (TCGA) and correlate expression with patient survival in different cancer types. We also discuss other recently published observations of relevance to the role of Treacle in cancer. In light of these new observations, we propose possible roles of Treacle in carcinogenesis and discuss its potential as a therapeutic target.