UVB radiation induces DNA damage generating several thymine photo-adducts (TDPs), which can lead to mutations and cellular transformation. The DNA repair pathways preserve genomic stability by recognizing and removing photodamage. These DNA repair side products may affect cellular processes. We previously synthesized novel thymine biomimetic thymine dimers (BTDs) bearing different alkane spacers between nucleobases. Thus, the present study investigates whether novel BTDs and their TDPs can modulate DNA damage safeguard pathways of primary keratinocytes and fibroblasts using 2D and 3D models. We found that the p53/p21^waf1 pathway is activated by BTDs and TDPs in primary cells similar to UVB exposure. Compound 1b can also induce the p53/p21^waf1 pathway in a 3D skin model. However, BTDs and TDPs exhibit distinct effects on cell survival. They have a protective action in keratinocytes, which maintain their clonogenic ability following treatments. Conversely, compounds induce pro-apoptotic pathways in fibroblasts that exhibit reduced clonogenicity. Moreover, compounds induce inflammatory cytokines mainly in keratinocytes rather than fibroblasts. Matrix metalloproteinase 1 is up-regulated in both cell types after treatments. Therefore, BTDs and TDPs can act in the short term as safeguard mechanisms helping DNA damage response. Furthermore, they have distinct biological effects depending on photodamage form and cell type.

Nicotinamide (NAM), the amide form of vitamin B3, has gained increasing attention in dermatology due to its potential role in both skin aging and non-melanoma skin cancer (NMSC) prevention. This review summarizes the biological rationale and current clinical evidence supporting the use of NAM and other NAD⁺ precursors in photoaging and cutaneous carcinogenesis. Chronic ultraviolet exposure induces DNA damage, oxidative stress, inflammation, immune dysregulation, and extracellular matrix remodeling, linking photoaged skin to increased susceptibility to actinic keratoses (AKs), squamous cell carcinoma (SCCs), and basal cell carcinoma (BCCs). Through the NAD⁺ salvage pathway, NAM contributes to the maintenance of intracellular NAD⁺ pools, thereby influencing energy metabolism, DNA repair, mitochondrial function, redox homeostasis, and the activity of NAD⁺-dependent enzymes. Preclinical studies indicate that NAM enhances DNA repair, reduces oxidative stress and inflammatory signaling, supports autophagy and mitophagy, and improves epidermal barrier function and extracellular matrix integrity. Clinically, the strongest evidence for anti-aging effects concerns topical NAM, which consistently improves wrinkles, texture irregularities, pigmentation, and barrier function. Oral NAM has demonstrated chemopreventive activity in high-risk patients with previous NMSC, particularly by reducing the incidence of new SCCs and AKs during active treatment. However, despite a strong mechanistic rationale, current evidence remains heterogeneous, and additional long-term, skin-focused clinical trials are needed to better define efficacy, safety, optimal dosing strategies, and patient selection.

Background/Objectives: Melanoma is the deadliest form of skin cancer. Resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) limits their clinical benefit, as these drugs remain palliative options when immunotherapies and targeted treatments fail. CSA/ERCC8 is a key component of transcription-coupled nucleotide excision repair (TC-NER), a pathway responsible for removing UV-induced DNA lesions. In principle, loss of a DNA repair factor would be expected to increase carcinogenesis. However, although CSA loss-of-function causes Cockayne Syndrome (CS), affected patients do not exhibit increased skin cancer incidence, suggesting that CSA impairment promotes apoptosis rather than tumor development. This paradox raises the possibility that CSA inhibition may selectively target melanoma cell survival pathways. Methods: The expression of CSA/ERCC8 was analyzed by qRT-PCR and Western blot. ERCC8 was silenced using antisense oligonucleotides. Cell viability, apoptosis, cell cycle progression, drug sensitivity, and DNA damage were assessed by functional assays, including IC50 determination and Bliss analysis for drug interactions. Results: We identified CSA/ERCC8 as a driver of melanoma chemoresistance. CSA was markedly overexpressed in primary and metastatic melanoma cells. ERCC8 silencing reduced proliferation, induced apoptosis, and significantly enhanced sensitivity to low doses of TMZ and DTIC while sparing normal cells. Conclusions: CSA represents a promising therapeutic target to overcome chemoresistance in melanoma. Its inhibition enhances the efficacy and selectivity of alkylating agents, supporting its potential as a salvage strategy for refractory disease and warranting further preclinical and clinical investigation.

Melanoma is the deadliest form of skin cancer, with resistance to alkylating agents such as Temozolomide (TMZ) and Dacarbazine (DTIC) further limiting the efficacy of these drugs, which remain palliative options when modern immunotherapies and targeted therapies fail. Here, we identify the Cockayne Syndrome group A (CSA) protein—a key component of Transcription-Coupled Nucleotide Excision Repair (TC-NER)—as a novel driver of melanoma chemo-resistance. CSA is markedly over-expressed in both primary and metastatic melanoma cells. Silencing CSA using Antisense Oligonucleotides (ASOs) robustly reduces melanoma cell proliferation, induces apoptosis, and—critically—sensitizes cells to low doses of TMZ and DTIC, while sparing normal cells. Notably, although CSA loss-of-function underlies Cockayne Syndrome (CS), a disorder characterized by defective repair of UV-induced DNA damage, these patients do not exhibit an increased incidence of skin cancer. This paradox highlights a unique biological context in which impaired CSA function promotes cellular apoptosis rather than carcinogenesis, suggesting that CSA inhibition could selectively cripple melanoma cells. These findings establish CSA as a promising therapeutic target to overcome chemo-resistance in melanoma. Combining CSA inhibition with alkylating agents offers a potential salvage strategy in patients with refractory disease and warrants further preclinical and clinical investigation.