Studies on the Functionality of the TC-NER ERCC6- M1097V Protein Variant Frequently Found in Louisiana PCa Patients upon UV Damage

ERCC6, also known as CSB (Cockayne Syndrome B), is a key protein involved in transcription-coupled nucleotide excision repair (TC-NER), a DNA repair process that removes lesions blocking RNA polymerase. ERCC6’s multifaceted roles include chromatin remodeling, transcription regulation, oxidative stress response, and coordination with other DNA repair proteins. Mutations in ERCC6 lead to Cockayne Syndrome and other neurodegenerative disorders, but some variants, such as M1097V, have been associated with cancer risk, particularly in African American (AA) populations. Recent studies have explored the functional impact of ERCC6 variants in prostate cancer (PCa), especially among AAs, who face higher incidence and more aggressive forms of the disease. A notable finding is that the M1097V variant increases cellular tolerance to UV damage, suggesting a possible evolutionary benefit but also a potential risk for mutagenesis when exposed to complex environmental carcinogens. Other ERCC6 mutations, such as S636N, located near regulatory regions, may alter repair activity, though their effects remain unclear. Given the high mutation burden in mismatch repair (MMR) and NER genes observed in AA PCa patients, a synthetic lethality strategy targeting both TC-NER and homologous recombination repair (HRR) pathways could be effective. This includes combining agents like CPT (cisplatin) with inhibitors of RAD54, such as J54. These approaches may offer alternatives to androgen deprivation therapy (ADT), which is often ineffective in advanced or treatment-resistant PCa common among AA men. This work underscores the importance of integrating genetic, environmental, and therapeutic insights to address PCa disparities.