Alpha-synuclein, associated with Parkinson’s, aids DNA repair in melanoma cells, suggesting a survival advantage.
Parkinson’s disease-associated protein
Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma
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Understanding Double-Strand Break (DSB):
Double-strand breaks (DSBs) represent severe DNA damage formation because they split both DNA helix strands at the same time. DSBs stand as severe DNA damage categories because these injuries disrupt genome structural integrity, leading to mutations and chromosomal alterations, which potentially end in lethal cell death.
Alpha-Synuclein’s Role in DNA Repair
Alpha-synuclein (αSyn) accumulates specifically in the nucleolus of melanoma cells where ribosomal DNA (rDNA) transcription occurs. The DNA damage response process draws αSyn to the proximity of these damage sites, known as DSBs while they are being repaired. When DSBs are induced experimentally in the nucleolus, αSyn accumulates in higher amounts at damaged areas, which implies its direct participation in the DNA Damage Response. The absence of αSyn leads cells to accumulate greater instances of DNA damage and hampers DNA repair efficiency because of its protective qualities.
Mechanism of Action
The DNA damage response pathway with ATM signaling functions as an upstream element from which αSyn performs its actions. ATM stands for Ataxia-Telangiectasia Mutated, a serine/threonine protein kinase that plays a central role in the DNA damage response (DDR).
The direct recruitment of 53BP1 depends on the aid provided by αSyn, which is vital for DSB repair at damaged sites. Genomic stability, together with efficient repair, requires such protein recruitment. The deficiency of αSyn in cells causes reduced 53BP1 protein recruitment, which results in elevated micronuclei numbers and diminished cellular proliferation together with reduced migration and invasion potential.
Implications for Parkinson’s Disease and Melanoma
Alpha synuclein plays multiple functions in neurodegenerative diseases and cancers, demonstrating an intricate relationship between these medical conditions. The accumulation of αSyn in Parkinson’s disease causes damage to neurons that eventually leads to their destruction. The higher levels of αSyn in Melanoma work to fix DNA, which leads to enhanced cancer cell development and survival. Research has demonstrated that the behavior of αSyn depends on specific conditions, which create novel therapeutic pathways to treat Parkinson’s disease and melanoma simultaneously.
Studies show that αSyn enables DNA repair activities at the nucleoli of melanoma cells, which creates a link between Parkinson’s disease pathology and cancer pathology. The discovery of this relationship creates new opportunities to develop treatments that target αSyn activity for managing Parkinson’s disease and melanoma progression.
Reference:
- Alpha-synuclein regulates nucleolar DNA double-strand break repair in melanoma https://pmc.ncbi.nlm.nih.gov/articles/PMC10802588/)
Source-Oregon Health & Science University