Xeroderma Pigmentosum Complementation Group C (XPC): Emerging Roles in Non-Dermatologic Malignancies

Abstract

Xeroderma pigmentosum complementation group C (XPC) is a DNA damage recognition protein essential for initiation of global-genomic nucleotide excision repair (GG-NER). Humans carrying germline mutations in the XPC gene exhibit strong susceptibility to skin cancer due to defective removal via GG-NER of genotoxic, solar UV-induced dipyrimidine photoproducts. However, XPC is increasingly recognized as important for protection against non-dermatologic cancers, not only through its role in GG-NER, but also by participating in other DNA repair pathways, in the DNA damage response and in transcriptional regulation. Additionally, XPC expression levels and polymorphisms likely impact development and may serve as predictive and therapeutic biomarkers in a number of these non-dermatologic cancers. Here we review the existing literature, focusing on the role of XPC in non-dermatologic cancer development, progression, and treatment response, and highlight possible future applications of XPC as a prognostic and therapeutic biomarker.

Keywords: base excision repair (BER); biomarker; bladder cancer; chemotherapy; lung cancer; nucleotide excision repair (NER); xeroderma pigmentosum (XP).

Figure 1

Schematic representation of the impact of XPC in dermatologic and non-dermatologic malignancies. Both XPC mutations and transcriptional regulation of XPC expression levels are described as impacting risk of the cancer development and response to treatment. Post-translational modifications of XPC include ubiquitination, SUMOylation and phosphorylation, which impact XPC expression levels and XPC function. XPC is a versatile DNA damage sensor, leading to differing binding affinities and DNA-XPC conformational changes for UV-induced DNA damage (“specific binding”, in concert with the UV-DDB complex, leading to GG-NER) and other DNA damage (“non-specific binding”, leading to other DNA repair pathways). Differential response of XPC to DNA damage leads to classical GG-NER or alternate DNA repair, altered transcriptional regulation, and DNA damage response ultimately impacting cancer risk and tumor cell toxicity. XPC, xeroderma pigmentosum group c; Ub, ubiquitin; SUMO, small ubiquitin-like modifier; P, phosphorylation site; DDB1, DNA damage-binding 1; DDB2, DNA damage binding 2; Cen2, centrin 2; HR23B, human UV excision repair protein RAD23; GG-NER, global genomic nucleotide excision repair; BER, base excision repair; MMR, mismatch repair; DSB, double strand break; HRR, homologous recombination repair; DDR, DNA damage response; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MM, multiple myeloma.

Figure 2

Schematic representation of XPC polymorphisms discussed in this manuscript along with alternate names/identifiers for the XPC polymorphisms most commonly studied in non-dermatologic cancers. Reference XPC gene (chr 3:p25.1) with polymorphisms was reproduced using the GRCh38 (hg38) sequencing using the UCSC genome browser tool. [(112) http://genome.ucsc.edu. Accessed 1/30/22]. Red = missense mutations, blue = 5’ or 3’ UTR variants, green = upstream of transcript variant.