DNA repair pathways

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. 

C. Bernstein, H. Bernstein, C. M. Payne and H. Garewal, DNA repair/ pro-apoptotic dual-role proteins in live major DNA repair pathways failsafe protection against carcinogenesis, Mutat. Res., 2002, 511(2), 145. 

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. 

Fig. 2. Synthetic lethal interaction between BER and FIR. BER and FIR are DNA repair pathways for SSB and DSB, respectively. Inhibition of BER or FIR alone does not cause cell death, while simultaneous inhibition of BER and FIR results in cell death.

The synthetic lethal effect between PARP inhibition and BRCAl/2 deficiency was first described in 2005 by Farmer et al and Bryant et al in preclinical studies (17, 18). BRCAl/2 deficient cell lines are more sensitive to PARP inhibition than BRCAl/2 proficient cell lines in colony formation assays and in xenograft models (17, 18). BER and HR are DNA repair pathways that carry out the repair of SSB and DSB, respectively. Inhibition of either pathway alone is not lethal, but loss of both pathways causes cell death (Fig. 2). Mechanistically, PARP inhibition blocks the activity of BER and leads to DNA SSB accumulation inside cells. When cells enter the next round of DNA replication, these DNA SSBs are converted to DNA DSBs which can be efficiently repaired through... 

Helleday T, Petermann E, Lundin C et al (2008) DNA repair pathways as targets for cancer therapy Nat Rev Cancer 8 193-204... 

The different enzymes involved in base excision repair (and other DNA repair pathways) are quite diverse. Even among the same family, sequence homology is usually... 

As an alternative to random mutagenesis by error-prone PCR, expression vectors containing the gene of interest may be propagated in mutator E. coli strains like XL 1-Red (Stratagene). This strains contains mutations in three DNA repair pathways and exhibits a more than 5000-fold increased spontaneous mutation rate (3.5 x 10-6), compared to wildtype E. coli (7 x 10-10) [22]. Provided that all mu-... 

Thus, there is substantial evidence to suggest that p53 plays a central role in the cellular response to DNA-damage. It is also clear that p53 can control the processing of Pt adducts. Additional experiments are needed to clarify exactly which function p53 fulfills in the management of the DNA repair pathway. 

Despite knowing the structures of all of the DNA lesions, it remains to be determined if any one lesion is more or less toxic to the cells. As discussed above, it was originally thought that DNA interstrand cross-links were the critical lesion. Once it was realized that these lesions are very rare, opinions shifted to suggest that DNA intrastrand cross-links are more cytotoxic. Unfortunately, there is no specific data that implicates either type of lesion in cytotoxicity. For some drugs like nitrosoureas, DNA repair pathways that remove only selected lesions (i.e., 0(6)-methylguanine DNA methyltransferase) have helped to define the role of a particular lesion [24], No separate pathway has been found for repair of a specific cisplatin adduct, so this approach has not been informative. A number of experiments have been performed in which specific adducts on defined DNA sequence, have been transfected into cells. This approach has shown that an adduct inhibits replication or transcription, but this does not directly address the question of mechanism of cytotoxicity. 

One of the major targets of SM alkylation is DNA which it can form both mono functional adducts and bifunctional crosslinks (Papirmeister et al, 1991c). Complementary DNA strand and intrastrand crosslinks occur after SM exposure (Walker, 1971). The crosslinking of cellular DNA underscores the importance of DNA repair pathways in preventing cytotoxicity of SM-exposed cells. These repair pathways include both the nucleotide and base excision pathways (Matijasevic and Volkert, 2007). 

The chemical transactions of DNA end joining are predictably similar to other DNA repair pathways and even to replication in that all of these processes manipulate base-pairing and phospho-diester bonds to create intact duplex molecules. However, the direct repair of DSBs presents biochemical challenges nniqne to these substrates. In this section, I consider both the general and the specific chemical requirements of nonhomologons DSB repair, how they are manifest in the two main pathways of repair, and the sometimes unusual properties of key enzymes that determine their function in these pathways. 

S.S. Parikh, C D. Mol, and J.A. Tainer. 1997. Base excision repair enzyme family portrait Integrating the structure and chemistry of an entire DNA repair pathway Structure 5 1543-1550. (PubMed)... 

A DNA repair pathway in which a damaged single-stranded segment of... 

A short outline of various DNA repair pathways has been presented. It is now possible to reveal several likely theories on how eating fruits and vegetables can reduce the occurrence of cancer. 

The involvement of DNA repair pathways in the development of drug resistance has become increasingly apparent over recent years from in vitro studies on tumor cell lines. Measurement of the expression of specific genes involved in DNA repair pathways in tumor samples has been used to assess the possible clinical significance of DNA repair. Elevated levels of p53 protein in tumors suggest mutation in the p53 gene. As p53 protein is involved in regulation of... 

Martin LP, Hamilton TC, Schilder RJ (2008) Platinum resistance the role of DNA repair pathways. Clin Cancer Res 14 1291-1295... 

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