Nucleotide excision repair mechanisms

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). 

In the present chapter, we have explained the beneficial role of trabectedin treatment against ovarian cancer s and we have shown its manageable adverse effects. We have concluded that compared to the significant risks of recurrence and resistance of ovarian cancer to the available therapeutic strategies, trabectedin can be used as an alternative therapeutic method. Moreover, there are numerous clinical studies on the efficacy and side effects of trabectedin and, therefore, we can easily take a decision about its most effective doses needed for obtaining anticancer effects. To conclude, it seems that transcription -coupled nucleotide excision repair mechanism plays a pivotal role in the anticancer effects of trabectedin. 

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.

The mechanism of eukaryotic excinucleases is quite similar to that of the bacterial enzyme, although 16 polypeptides with no similarity to the E. coli excinuclease subunits are required for the dual incision. As described in Chapter 26, some of the nucleotide-excision repair and base-excision repair in eukaryotes is closely tied to transcription. Genetic deficiencies in nucleotide-excision repair in humans give rise to a variety of serious diseases (Box 25-1). 

Gillet, L. C. J., and Scharer, O. D. Molecular mechanisms of mammalian global genome nucleotide excision repair. Chem. Rev. 106, 253-276, 2006. 

The maintenance of the integrity of the genetic message is key to life. Consequently, all cells possess mechanisms to repair damaged DNA. Three types of repair pathways are direct repair, base-excision repair, and nucleotide-excision repair (Figure 27.47). 

There are six general mechanisms of DNA repair direct repair (DR), nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR), homologous recombination repair (HRR), and non-homologous end joining (NHEJ). 

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. 

Evans E,Moggs JG, Hwang JR,EglyJM,Wood RD (1997) Mechanism of open complex and dual incision formation by human nucleotide excision repair factors. EMBO J 16 6559-73... 

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).

In addition, and while UVR-mediated DNA damage occurs in aquatic autotrophic organisms [168,193-196], repair mechanisms of the DNA molecule (see Chapter 9) are also present [193]. However, the presence of one or other mechanism (i.e., photoreactivation, nucleotide excision repair or recombination repair) is clearly dependant on the species under study and the radiation conditions at which the cells are exposed (see Chapter 9). 

Fousteri, M., and Mullenders, L. H. (2008). Transcription-coupled nucleotide excision repair in mammalian cells Molecular mechanisms and biological effects. Cell Res 18, 73-84. 

Shuck, S. C., Short, E. A., and Turchi, J. J. (2008). Eukaryotic nucleotide excision repair From understanding mechanisms to influencing biology. Cell Res 18, 64-72. 

Mechanisms of Base Excision Repair and Nucleotide Excision Repair... 

Y., Masutani, C., Iwai, S., and Hanaoka, F. (2001) A multistep damage recognition mechanism for global genomic nucleotide excision repair. Genes Dev., 15, 507-521. 

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