The RAD30 cancer susceptibility gene

Carty, Michael P.; Glynn, Macdara; Maher, Martha B.; Smith, Thomas W.; Yao, J.; Dixon, Kathleen; McCann, John D.; Rynn, L.; Flanagan, Annabelle M

doi:10.1042/bst0310252

Cited by 12 publications

(8 citation statements)

References 42 publications

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“…However, despite its association with skin cancer, relatively little is known about the status of POLH in skin tumours (25). In the present study, the POLH genotype and mRNA expression pattern was analysed in a cohort of skin cancer patients.…”

Section: Introductionmentioning

confidence: 99%

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

Flanagan

Rafferty²,

O’Neill³

et al. 2007

Int J Mol Med

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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.

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Section: Introductionmentioning

confidence: 99%

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

Flanagan

Rafferty²,

O’Neill³

et al. 2007

Int J Mol Med

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“…The primary role for PolH is the bypass of UV photoproducts, which performs in a primarily error-free manner. The active site of PolH is very open, allowing for full accommodation of a thymine-thymine cyclobutane pyrimidine dimer and preferentially incorporates two adenines during replication (93-95). PolH also appears to contribute to the error-free bypass of (6-4) pyrimidine-pyrimidone photoproducts (78, 96).…”

Section: Dna Polymerase Etamentioning

confidence: 99%

DNA polymerases in the mitochondria A critical review of the evidence

Copeland¹

2017

Front Biosci

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Since 1970, the DNA polymerase gamma (PolG) has been known to be the DNA polymerase responsible for replication and repair of mitochondrial DNA, and until recently it was generally accepted that this was the only polymerase present in mitochondria. However, recent data has challenged that opinion, as several polymerases are now proposed to have activity in mitochondria. To date, their exact role of these other DNA polymerases is unclear and the amount of evidence supporting their role in mitochondria varies greatly. Further complicating matters, no universally accepted standards have been set for definitive proof of the mitochondrial localization of a protein. To gain an appreciation of these newly proposed DNA polymerases in the mitochondria, we review the evidence and standards needed to establish the role of a polymerase in the mitochondria. Employing PolG as an example, we established a list of criteria necessary to verify the existence and function of new mitochondrial proteins. We then apply this criteria towards several other putative mitochondrial polymerases. While there is still a lot left to be done in this exciting new direction, it is clear that PolG is not acting alone in mitochondria, opening new doors for potential replication and repair mechanisms.

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“…Carcinogens also include various forms of radiation. Ultraviolet (UV) radiation directly reacts with DNA and generates bulky DNA lesions such as cyclobutane pyrimidine dimers (CPD) and 6-4 pyrimidone photoproducts (6-4PP) [6,7]. If left unrepaired, they may induce mutations and eventually cause skin cancers.…”

Section: Introductionmentioning

confidence: 99%

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

et al. 2020

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Background: Acetaldehyde, produced upon exposure to alcohol, cigarette smoke, polluted air and sugar, is a highly reactive compound that is carcinogenic to humans and causes a variety of DNA lesions in living human cells. Previously, we reported that acetaldehyde reacts with adjacent deoxyguanosine residues on oligonucleotides, but not with single deoxyguanosine residues or other deoxyadenosine, deoxycytosine, or thymidine residues, and revealed that it forms reversible intrastrand crosslinks with the dGpdG sequence (GG dimer). Results: Here, we show that restriction enzymes that recognize a GG sequence digested acetaldehyde-treated plasmid DNA with low but significant efficiencies, whereas restriction enzymes that recognize other sequences were able to digest such DNA. This suggested that acetaldehyde produced GG dimers in plasmid DNA. Additionally, acetaldehyde-treated oligonucleotides were efficient in preventing digestion by the exonuclease function of T4 DNA polymerase compared to non-treated oligonucleotides, suggesting structural distortions of DNA caused by acetaldehyde-treatment. Neither in vitro DNA synthesis reactions of phi29 DNA polymerase nor in vitro RNA synthesis reactions of T7 RNA polymerase were observed when acetaldehyde-treated plasmid DNA was used, compared to when non-treated plasmid DNA was used, suggesting that acetaldehyde-induced DNA lesions inhibited replication and transcription in DNA metabolism. Conclusions: Acetaldehyde-induced DNA lesions could affect the relative resistance to endo-and exo-nucleolytic activity and also inhibit in vitro replication and in vitro transcription. Thus, investigating the effects of acetaldehydeinduced DNA lesions may enable a better understanding of the toxicity and carcinogenicity of acetaldehyde.

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The RAD30 cancer susceptibility gene

Cited by 12 publications

References 42 publications

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

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

DNA polymerases in the mitochondria A critical review of the evidence

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

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