Repair, nucleotide excision

AP sites, left unrepaired, impede the progression of DNA polymerases during DNA replication and can be mutagenic in the synthesis of both DNA and RNA. AP sites can also be converted to toxic lesions by spontaneous rearrangements that produce structures that can crosslink with proteins and lipids. They can also create toxic lesions by the activities of topoisomerase I and topoisomerase II. In addition, the processing of AP sites by the BER proteins can produce structures that are toxic. Hence, to prevent these deleterious events from occurring, the BER process is likely coordinated and each step involves a handing off from one enzyme in the pathway to the next. 

Nucleotide excision repair (NER) removes an assortment of different types of DNA damage. It removes chemical adducts introduced by exposure to chemical 

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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.

Wood RD Nucleotide excision repair in mammalian cells. J Biol Chem 1997 272 23465. 

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. 

S. A. The 19S complex of the proteasome regulates nucleotide excision repair in yeast. Genes. Dev. 2001, 15, 1528-1539. 

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). 

Answer B, Nucleotide excision repair of thymine (pyrimidine) dimers is deficient in XP... 

Rad26 Rad26p S. cerevisiae Deflp, Associates with RNA pol II Transcription coupled nucleotide excision repair [319,320]. 

CSB/ERCC6 CSB Human Associates with a subset of Pol II complexes Mutation causes Cockayne syndrome, a defect in transcription coupled nucleotide excision repair [321,322]. Human Rad26p homolog... 

Radi 6 Radl6p S. cerevisiae Rad7p, AbHp Global genome nucleotide excision repair [76,323,324]. 

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.

DNA repair pathways can be divided into those that respond to SSB and those that respond to DSB. SSB repair pathways include base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER). DSB repair pathways include nonhomologous end joining (NHEJ) and homologous recombination (HR). The proteins involved in these DNA repair pathways are shown in Fig. 1. 

DNA adducts most likely reflects increased DNA repair such as nucleotide excision repair and postreplication repair including translesion synthesis, gap filling, and template switching during replication (27,28). 

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