Nucleotide excision repair human

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.

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... 

Furuta T, Ueda T, Aune G et al. Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res 2002,62 4899 902. 

Indeed, Ellis s group provided some very nice examples of the application of Zn NMR spectroscopy when applied to proteins, such as the Minimal DNA Binding Domain of Human Nucleotide Excision Repair Protein XPA and the Human Carbonic Anhydrase. ... 

Most microorganisms have redundant pathways for the repair of cyclobutane pyrimidine dimers— making use of DNA photolyase and sometimes base-excision repair as alternatives to nucleotide-excision repair—but humans and other placental mammals do not. This lack of a back-up to nucleotide-excision repair for the removal of pyrimidine dimers has led to speculation that early mammalian evolution involved small, furry, nocturnal animals with little need to repair UV damage. However, mammals do have a path-... 

FIGURE 25-24 Nucleotide-excision repair in E. coli and humans. The general pathway of nucleotide-excision repair is similar in all organisms. (J) An excinuclease binds to DNA at the site of a bulky lesion and cleaves the damaged DNA strand on either side of the lesion. (2) The DNA segment—of 13 nucleotides (13 mer) or 29 nucleotides (29 mer)—is removed with the aid of a helicase. (3) The gap is filled in by DNA polymerase, and the remaining nick is sealed with DNA ligase. 

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). 

The repair of stalled replication forks entails a coordinated transition from replication to recombination and back to replication. The recombination steps function to fill the DNA gap or rejoin the broken DNA branch to recreate the branched DNA structure at the replication fork. Lesions left behind in what is now duplex DNA are repaired by pathways such as base-excision or nucleotide-excision repair. Thus a wide range of enzymes encompassing every aspect of DNA metabolism ultimately take part in the repair of a stalled replication fork. This type of repair process is clearly a primary function of the homologous recombination system of every cell, and defects in recombinational DNA repair play an important role in human disease (Box 25-1). 

When Pol II transcription halts at the site of a DNA lesion, TFIIH can interact with the lesion and recruit the entire nucleotide-excision repair complex. Genetic loss of certain TFIIH subunits can produce human diseases. Some examples are xeroderma pigmentosum (see Box 25-1) and Cockayne s syndrome, which is characterized by arrested growth, photosensitivity, and neurological disorders. ... 

Excision repair. The E. coli mismatch repair is a type of excision repair. However, a different nucleotide excision repair system (NER) is utilized by all organisms from bacteria to human to remove a variety of defects. These include thymine dimers, photohydrates, oxidized bases, adducts of cisplatin (Box 5-B), mutagens derived from polycyclic aromatic compounds,683 and poorly recognized OC mismatched pairs.692 In E. coli this excision repair process depends upon proteins encoded by genes UvrA, B, C, and D and also DNA polymerase I and DNA ligase.693 695a A dimer of protein UvrA forms a complex with helicase UvrB (Eq. 27-22).696 696a... 

Both yeast and human cells have similar but more complex systems of nucleotide excision repair.700-703... 

While defects in protein XPD often cause typical XP symptoms, some defects in the same protein lead to trichothiodystrophy (TTD, brittle hair disease). The hair is sulfur deficient, and scaly skin (ichthyosis, Box 8-F), mental retardation, and other symptoms are observed.0 Like their yeast counterparts (proteins RAD3 and RAD25), XPB and XPD are both DNA helicases.0 They also constitute distinct subunits of the human transcription factor TFIIHP, which is discussed in Chapter 28. It seems likely that XPD is involved in transcription-coupled repair (TCR) of DNA.° °i-s This is a subpathway of the nucleotide excision repair (NER) pathway, which allows for rapid repair of the transcribed strand of DNA. This is important in tissues such as skin, where the global NER process may be too slow to keep up with the need for rapid protein synthesis. Transcription-coupled repair also appears to depend upon proteins CSA and CSB, defects which may result in the rare cockayne syndrome.13 0 4 11 Patients are not only photosensitive but have severe mental and physical retardation including skeletal defects and a wizened appearance. 

The product yields in y-irradiated DNA are given in Tables 12.5-12.7. FAPY-G has always been observed, but 8-oxo-G yields were extremely low, when y-ir-radiations were carried out under N2. This may serve as a caveat for the common practice to use 8-oxo-G as a kind of marker for free-radical DNA damage (for assays see Chap. 13.2). Besides the other products reported in Table 12.5, 8 cG lesions per 106 bases are formed per Gy in y-irradiated N20-saturated DNA (50 pg ml-1) solution (Dizdaroglu et al. 2001a corresponding to 1.6 x 10 9 mol J-1), and this lesion has also been observed in y-irradiated cultured human cells (Dizdaroglu 1986 for its elimination by nucleotide excision repair see Kuraoka et al. 2000). 

Hartwig, A., Groblinghoff, U.D., Beyersmann, D. et al. (1997) Interaction of arsenic(III) with nucleotide excision repair in UV-irradiated human fibroblasts. Carcinogenesis, 18(2), 399-405. 

Finally, in addition to nucleotide excision repair and base excision repair, an alternative repair pathway exists to remove PyroPyr and (6 ) photoproducts in some organisms, including Schizosaccharomyces pombe. In this alternative pathway, an enzyme called UV dimer endonuclease cleaves DNA immediately 5 to the damaged lesion. The damage is then removed by a 5 to 3 exonuclease (26, 27). Additionally, AP endonucleases, like Nfo in E. coli and APEl in humans, have the ability to incise immediately 5 to nonbulky lesions caused by oxidative damage and initiate excision of the lesion by a 5 to 3 exonuclease (28). 

Figure 6 Nucleotide excision repair in (A) E. coli and (B) humans. There are five basic steps of nucieotide excision repair (1) damage recognition, (2) dual incisions, (3) release of the excised oligomer, (4) repair synthesis to fill in the gap, and (5) ligation.

Translesion synthesis with DNA Pol of the A-acetyl-2-aminofluorene adduct of guanosine (88) is inefficient with templates containing (88). In the presence of the Revl protein, translesion synthesis occurs and dCTP is the major nucleotide incorporated opposite it, and studies with a mutant DNA Pol I gave similar results. Benzo[a]pyrene is a potent environmental carcinogen, which when metabolised leads to u t -benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide anti-BPDE). With dG, the major lesion is (+)-tra w-a h-B[a]P-A -dG, (89), and is usually repaired by the nucleotide excision repair (NER) pathway. The translesion synthesis past (89) has been examined with a number of polymerases. With human RNA Pol II, (89) is a block to synthesis, whilst DNA Pol k preferentially incorporated the correct nucleotide. In yeast cells, Pol induced a large number of mutations involving Pol p, whilst Pol p alone contributed to 1-3 deletions or insertions. The NER of (89) with UvrB proteins was also studied. ... 

R461 K. Morikawa and M. Shirikawa, Three-Dimensional Structural View of Damaged-DMA Recognition T4 Endonuclease V, E. coli Vsr, Protein, and Human Nucleotide Excision Repair Factor XPA , Mutat. Res., 2000,460, 257... 

Zn solid-state NMR spectroscopic studies of the minimal DNA binding domain of human nucleotide excision repair protein XPA have been reported. ... 

The two diastereoisomers of the 5 -8-adenosine cyclonucleoside have been incorporated into DNA and shown to block DNA replication by various polymerases when present in the template strand. Both isomers were substrates for the human nucleotide excision-repair enzyme, though the R diastereoisomer was repaired more efficiently. 

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. 

Reardon JT, Bessho T, Kung HC, Bolton PH, San car A (1997) In vitro repair of oxidative DNA damage by human nucleotide excision repair system possible explanation for neurodegeneration in Xeroderma Pigmentosum patients. Proc Natl Acad Sci USA 94 9463-8... 

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