Nucleotide excision repair pathway

Brooks PJ, Wise DS, Berry DA, Kosmoski JV, Smerdon MJ, Somers RL, Mackie H, Spoonde AY, Ackerman EJ, Coleman K,TaroneRE, Robbins JH (2000) The oxidative DNA lesion 8,5 -(S)-cyclo-2 -de-oxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells. J Biol Chem 275 22355-22362 Brown AU, Todd AR (1952) Nucleotides 10. Some observations on the structure and chemical behaviour of the nucleic acids. J Chem Soc 52-58... 

DNA Repair. A connection between p53 and DNA repair was observed in p53-deficient cells that exhibited less global DNA repair [197-199] (but see [200]), as well as a reduced capacity to reactivate cisplatin- and UV-damaged reporter plasmids [173][201 ][202]. Furthermore, pretreatment with low levels of UV activated a protective response in which the levels of repair activity were elevated, an effect not observed in p53-deficient cells [202] [203]. It is possible that the p53 protein is directly involved in removing DNA damage since the protein recognizes both irradiated DNA and mismatches [ 162]. There is also evidence that p53 can interact with several components of the excinuclease, including RPA and the TFIIH-associated factors XPB and XPD [204] [205]. So far, however, there is no evidence to demonstrate a direct role for p53 in the nucleotide excision repair pathway. 

Sensitive to genotoxic carcinogens that are reactive to the nucleotide excision repair pathway... 

The nucleotide excision repair pathway recognizes specific distortions in DNA to find the damage and repair it. It is difficult to see how this is achieved when the damage is imbedded in DNA compacted with chromatin. Studies performed in vitro and in vivo indicate that DNA damage present in chromatin or within the nucleosome is actually shielded from repair enzymes. Models have been proposed that invoke chromatin remodeling enzymes to help the NER proteins gain access to the damage, and there is experimental evidence to support them. Several different... 

Known DNA repair-deficient syndromes mainly affect the nucleotide excision repair pathway and the mechanisms for strand break repair. No human disorders caused by inherited BER deficiencies have been identified. The most hkely explanations are based on the generated mice knock out models. Deficiency of a single glycosylase may not cause an overt phenotype as the substrates can be repaired by other glycosylases or by other repair systems. In contrast, knock out of BER core proteins often induces embryonic lethahty. 

Inherited defects in the nucleotide excision-repair pathway, as in individuals with xeroderma pigmentosum, predispose them to skin cancer. Inherited colon cancer frequently is associated with mutant forms of proteins essential for the mismatch repair pathway. 

UV rays derived from the skin induce an increased incidence of all skin cancers, including squamous cell carcinoma, basal cell carcinoma, and malignant melanoma of the skin. The wavelength of UV light most associated with skin cancer is UVB (280-320 nm), which forms pyrimidine dimers in DNA. This type of DNA damage is repaired by nucleotide excision repair pathways that require products of at least 20 genes. With excessive exposure to the sun, the nucleotide excision repair pathway is overwhelmed, and some damage remains unrepaired. 

Notably, photodimers of the cyclobutane type are cleaved by irradiation with far-UV light (240 nm) with a quantum yield of almost unity by way of the so-called [2+2] cycloreversion reaction. In living cells, dimer lesions can be repaired by the nucleotide excision repair pathway, which is based on the excision of a small piece of DNA around the lesion. Lesions not removed from the genome lead to cell death or mutagenesis. 

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