Studies on the functionality of the TC-NER ERCC6-M1097V protein variant frequently found in Louisiana patients with PCa upon UV damage

TL;DR

This study investigates how a specific ERCC6 protein variant, M1097V, affects DNA repair and cancer risk in Louisiana African American men with prostate cancer.

Contribution

The paper explores the functional impact of the ERCC6-M1097V variant and proposes a synthetic lethality strategy for prostate cancer treatment.

Findings

The M1097V variant increases cellular tolerance to UV damage, potentially increasing mutagenesis risk.

ERCC6 mutations like S636N may alter DNA repair activity, though their effects are not fully understood.

A synthetic lethality strategy targeting TC-NER and HRR pathways could be effective for treating prostate cancer.

Abstract

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 prostate cancer (PCa) in African Americans (AAs) in Louisiana. Recent studies have explored the functional impact of ERCC6 variants in 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 not only a possible evolutionary benefit but also a potential risk for mutagenesis when exposed to complex environmental carcinogens. Other ERCC6 mutations, such as S636N (also only found in Louisiana PCa), 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 patients with PCa, a synthetic lethality strategy targeting both TC-NER and homologous recombination repair (HRR) pathways could be effective. This includes combining agents like CDDP (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.

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