Excision repair pathway

Excision Repair. Some groups of enzymes (light-independent) are apparently organized to act cooperatively to recognize DNA lesions, remove them, and correctly replace the damaged sections of DNA. The most comprehensively studied of these is the excision repair pathway. 

Bennett, R.A., Wilson, D.M., 3rd, Wong, D., and Demple, B. (1997) Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway. Proc. Natl. Acad. Sci. USA 94, 7166-7169. 

Selvakumaran M, Pisareik DA, Bao R et al. Enhaneed eisplatin eytotoxieity by disturbing the nueleotide excision repair pathway in ovarian eaneer eell lines. Cancer Res 2003 63 1311-1316. 

FIGURE 25-23 DNA repair by the base-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. 

It is more likely that p53 influences repair in a regulatory capacity. One link between p53 and NER was made with the observation that the p5 3-regulated Gadd45 binds to PCNA, a component of both replication and repair [206]. Overexpression of Gadd45 provided a small level of protection from cisplatin [207], whereas Gadd45 antisense DNA sensitized human colon carcinoma cells to cisplatin, an effect which was associated with a decrease in repair [201], It was hypothesized that the Gadd45 protein could interact directly with the repair proteins because it stimulated repair synthesis in nuclear extracts [206] however, this result could not be reproduced under a variety of experimental conditions [208][209], Thus, it seems likely that there are still some as yet unidentified factors which link p53 and the 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... 

Seeberg E, Eide L, Bjoras M. The base excision repair pathway. Trends Biochem. Sci. 1995 20 391-397. 

The enkaryotic nncleotide excision repair pathway. Biochimie 2003 85 1083-1099. 166. 

Alieva JL, Zuo S, Hurwitz J, Doetsch PW. In vitro reconstitution of the Schizosaccharomyces pombe alternative excision repair pathway. Biochemistry 2000 39(10) 2659-2666. 

D. The damage to DNA caused by ultraviolet light (pyrimidine dimers) can be repaired by the excision repair pathway. In some cases, the missing enzyme is a repair endonuclease. 

Excision repair pathways for removing base damage... 

One of the first important insights in the field of DNA repair was made after isolation of E. coli mutants with exceptional sensitivity to UV light [2] and subsequent mapping of mutations in genes designated uvrA, B, and C [3]. This led to the model of nucleotide excision repair [4,5]. Later the base excision repair pathway was exposed when Lindahl and coworkers [6,7] discovered a series of bacterial enzymes that recognized and removed modified nucleotides by a DNA N-glycosylase reaction. 

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. 

The use of the repair-proficient E. coli strain WP2 (pKMlOl) allows the detection of crosslinking agents that require an intact excision repair pathway to generate mutations, and this strain may also be selected. 

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