Nucleotide excision-repair of DNA

Araujo, S.J., Tirode, F., Coin, F., Pospiech, H., Syvaoja, J.E., Stucki, M., Hubscher, U., Egly, J.M., and Wood, R.D. (2000) Nucleotide excision repair of DNA with recombinant human proteins definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev., 14, 349-359. 

Batty, D., and R. Wood. 2000. Damage recognition in nucleotide excision repair of DNA. Gene 241 193-204. 

Wang, Z., Wu, X., and Friedberg, E. C. (1991). Nucleotide excision repair of DNA by human cell extracts is suppressed in reconstituted nucleosomes. / Biol. Chem. 266, 22472-22478. 

Rubbi CP, Milner J. p53 is a chromatin accessibility factor for nucleotide excision repair of DNA damage. EMBO J 2003 22 975-986. 

Excinuclease The excision nuclease involved in nucleotide exchange repair of DNA. 

Comparison between DNA repair and phospholipid repair The processes that can lead to DNA damage and the type of damage are described in Chapter 9 and Appendix 9.6. The repair processes involve removal of the specific nucleotide(s) by an exonuclease and replacement of the nucleotide by a DNA polymerase. Since the strand must be broken to remove the damage (by an endonuclease) these parts of the strand must be repaired by a ligase. The process is known as excision-repair. Of interest, there is a degree of similarity between the removal of damaged polyunsaturated fatty acids from phospholipids in membranes and replacement with a new fatty acid by two enzymes, a deacylase and an acyltransferase (see above and Chapter 11), and excision-repair of DNA. 

Figure 1. Schematic presentation of (A) DNA repair mechanisms 1. Photoreactivation also known as photoenzymatic repair, and 2. Nucleotide excision repair where the lesion damaged by exposure to UV-B is reversed (photoreactivation) or expelled (nucleotide excision repair) (B) DNA damage tolerance mechanisms 1. Dimer bypass and 2. Recombinational repair where replication proceeds around the lesion and the gap is filled in by adenine (dimer bypass) or a homologous sequence is inserted (recombinational repair).

TFIIH also partidpates in another important cellular function, namely nucleotide excision repair of damaged DNA. This function accounts for the observation that transcription and the removal of bulky base adducts by nucleotide excision repair (NER) are coupled. An increased repair of DNA damage by NER is observed while a gene is being transcribed. During transcription-coupled repair, TFIIH assembles with other repair proteins into a large repair complex, allowing for the removal of DNA adducts. 

Selby, C.P. and Sancar, A. (1990) Transcription preferentially inhibits nucleotide excision repair of the template DNA strand in vitro. J. Biol. Chem., 265, 21330-21336. 

Ura, K., Araki, M., Saeki, H., Masutani, G., Ito, T., Iwai, S., Mizukoshi, T., Kaneda, Y., and Hanaoka, F. (2001). ATP-dependent chromatin remodeling facilitates nucleotide excision repair of UV-induced DNA lesions in synthetic dinucleosomes. EMBO J. 20, 2004-2014. 

Crosslinks result from the reaction of a bifunctional electrophilic species with DNA bases and imply a covalent link between two adjacent DNA strands which inhibits DNA replication. Primary targets within bases are N7 and 06 in guanine and N3 in cytosine. The initial lesions are removed by the suicide enzyme alkyltrans-ferase, whereas nucleotide excision repair is needed for frilly established crosslinks. 

Figure 36-24. Nucleotide excision-repair. This mechanism is employed to correct larger defects in DNA and generally involves more proteins than either mismatch or base excision-repair. After defect recognition (indicated by XXXX) and unwinding of the DNA encompassing the defect, an excision nuclease (exinucle-ase) cuts the DNA upstream and downstream of the defective region. This gap is then filled in by a polymerase (5/e in humans) and religated.

Kasparkova, J. Zehnulova, J. Farrell, N. Brabec, V. DNA interstrand crosslinks of novel antitumor trinuclear platinum complex BBR. Conformation, recognition by HMG-domain proteins and nucleotide excision repair. J Biol Chem 2002, 277, 48076-48086. 

DNA base damage is also frequent after radiation (Ward, 1986). As compared to ssb, this DNA lesion is regarded as a possible source of mutation and is repaired through specific DNA repair pathways, such as base excision repair and nucleotide excision repair. 

Ultraviolet light induces the formation of dimers between adjacent thymines in DNA (also occasionally between other adjacent pyrimidines). The formation of thymine dimers interferes with DNA rephcation and normal gene expression. Thymine dimers are eliminated from DNA by a nucleotide excision-repair mechanism (Figure 1-2-4). 

Fig. 1. Proteins in DNA repair pathways. DNA repair proteins are listed for each of the following pathways BER (Base Excision Repair), NER (Nucleotide Excision Repair), MMR (Mismatch Repair), HR (Homologous Recombination), and NHEJ (Nonhomologous End Joining). PARP1/2 and BRCA1/2 are relevant in BER and HR pathways, respectively.

Nucleotide excision repair involves the removal of the region surrounding a modified base or single-strand break by nuclease-mediated excision (cutting) of the DNA strand on either side of the lesion followed by filling of the resulting gap. 

The answer is C. Thymine dimers are repaired by the process of nucleotide excision repair, which involves many enzyme activities that recognize the mutated structure, cut the DNA strand on both sides of the mutation, remove (excise) the affected fragment, and then refill the gap. One of the major genes leading to xeroderma pigmentosoum encodes a specific excinuclease. 

Tobacco accounts for about 90% of lung cancers. Some tobacco carcinogens induce DNA adducts that are repaired by the nucleotide excision repair (NER) pathway (3). The lowest DNA repair capacity (DRC), measured in peripheral blood lymphocytes by the host cell reactivation assay (HCR), was observed in lung cancer patients who were less than 60 years old, female, or lighter smokers, and in those with a family history of cancer (4,5). 

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