The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin

Abstract

Abstract. Skin cancer, the most common cancer in the general population, is strongly associated with exposure to the ultraviolet component of sunlight. To investigate the relationship between DNA damage processing and skin tumour development, we determined the POLH status of a cohort of skin cancer patients. The human POLH gene encodes DNA polymerase Ë (polË), which normally carries out accurate translesion synthesis past the major UV-induced photoproduct, the dithymine cyclobutane dimer. In the absence of active polË in xeroderma pigmentosum variant (XPV) patients, mutations accumulate at sites of UV-induced DNA damage, providing the initiating step in skin carcinogenesis. Forty patients diagnosed with skin cancer were genotyped for polymorphisms in the POLH protein-coding sequence, using glycosylase-mediated polymorphism detection (GMPD) and direct DNA sequencing of POLH PCR products derived from white blood cell genomic DNA. All individuals carried the wild-type POLH sequence. No POLH mutations were identified in genomic DNA from skin tumours derived from 15 of these patients. As determined by RT-PCR, POLH mRNA was expressed in all normal and skin tumour tissue examined. PolË protein was also detectable by Western blotting, in two matched normal and skin tumour extracts. An alternatively spliced form of POLH mRNA, lacking exon 2, was more readily detected in skin tissue than in white blood cells from the same patient. Real-time PCR was used to quantify POLH expression in matched normal and skin tumour-derived mRNA from a series of patients diagnosed with either basal or squamous cell carcinoma. Compared to matched normal skin tissue from the same patient, 1 of 7 SCC, and 4 of 10 BCC tumours examined showed at least a 2-fold reduction in POLH expression, while 1 of 7 SCC, and 3 of 10 BCC tumours showed at least a 2-fold increase in POLH expression. Differences in gene expression, rather than sequence changes may be the main mechanism by which POLH status varies between normal and skin tumours in the population under investigation. Knowledge of the POLH status in skin tumours could contribute to an understanding of the role of this gene in the development of the most common cancer in the general population.

The Regulation of DNA Damage Tolerance by Ubiquitin and Ubiquitin-Like Modifiers

“…Polη seems also to be involved in the cellular response after treatment with nucleoside analogs, which are commonly used in the clinic as cancer drugs ( Chen et al, 2006 ). Interestingly, mutations in polη are hardly found in patients with sporadic skin carcinomas ( Glick et al, 2006 ; Flanagan et al, 2007 ; Lange et al, 2011 ) but its overexpression has been reported ( Albertella et al, 2005b ). Polη ortholog, polι, has been found to be elevated in breast cancer cells and in these cell lines a reduced mutation frequency was recorded when the polymerase was depleted in vitro ( Yang et al, 2004 ).…”

Biological and Therapeutic Relevance of Nonreplicative DNA Polymerases to Cancer

“…Another study assessed gene expression profiles in nonsmall-cell lung cancer biopsies and reported an upregulation of pol g (246). Furthermore, in a small cohort of skin cancer patients, pol g was found downregulated in 4 of the 10 examined basal-cell carcinoma biopsies and upregulated in 3 of 10 specimens, whereas only 1 out of 7 squamous cell cancer samples exhibited a significant increase in pol g (77).…”

“…Additional variants of the POLH gene have been suggested as low-penetrance alleles predisposing for malignant melanoma (65). In contrast, no mutations or variations in the POLH gene were found in a panel of basal and squamous skin cancers (77,87).…”

DNA polymerase η is regulated by poly(rC)-binding protein 1 via mRNA stability

“…Mutation of the POLH gene is associated with human syndrome, Xeroderma Pigmentosum Variant (XPV) [15–17]. XPV patients are prone to skin cancer [18–20]. Consistently, repression of POLH expression is observed in various types of skin cancer [18].…”

“…XPV patients are prone to skin cancer [18–20]. Consistently, repression of POLH expression is observed in various types of skin cancer [18]. In addition to its role in TLS, POLH is necessary for hypermutation of immunoglobulin genes [21, 22] and for maintenance of genome stability [23–26].…”