Xeroderma Pigmentosum Group C Protein Complex Is the Initiator of Global Genome Nucleotide Excision Repair

Sugasawa, Kaoru; Ng, Jessica M.Y.; Masutani, Chikahide; Iwai, Shigenori; Spek, Peter J. van der; Eker, A.P.M.; Hanaoka, Fumio; Bootsma, D.; Hoeijmakers, Jan H.J.

doi:10.1016/s1097-2765(00)80132-x

Cited by 795 publications

(670 citation statements)

References 41 publications

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“…There is evidence that it plays a role in the initial steps of NER, where it is involved in damage recognition/verification [1][2][3]. We have proposed an additional important function for XPA, that of a processivity factor needed to confer a processive mechanism of action on the endonucleases, XPF and XPG, involved in NER [4,5].…”

Section: Introductionmentioning

confidence: 96%

Domains in the XPA protein important in its role as a processivity factor

Bartels

Lambert

2007

Biochemical and Biophysical Research Communications

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XPA is a protein essential for nucleotide excision repair (NER) where it is thought to function in damage recognition/verification. We have proposed an additional role, that of a processivity factor, conferring a processive mechanism of action on XPF and XPG, the endonucleases involved in NER. The present study was undertaken to examine the domain(s) in the XPA gene that are important for the ability of the XPA protein to function as a processivity factor. Using site-directed mutagenesis, mutations were created in several of the exons of XPA and mutant XPA proteins produced. The results showed that the DNA binding domain of XPA is critical for its ability to act as a processivity factor. Mutations in both the zinc finger motif and the large basic cleft in this domain eliminated the ability of XPA to confer a processive mechanism of action on the endonucleases involved in NER.Keywords xeroderma pigmentosum; XPA protein; DNA repair; processive mechanism of action Though the XPA protein is a key component in NER, its precise function in this repair pathway is not clear. There is evidence that it plays a role in the initial steps of NER, where it is involved in damage recognition/verification [1][2][3]. We have proposed an additional important function for XPA, that of a processivity factor needed to confer a processive mechanism of action on the endonucleases, XPF and XPG, involved in NER [4,5]. Proteins can locate target sites on DNA by two distinctive mechanisms: (1) a processive mechanism in which a protein first binds to a random site on DNA and then translocates to a specific site by a facilitated-diffusion process in which it slides or hops along the DNA; or (2) a distributive mechanism, in which a protein has no affinity for non-target DNA and locates target sites by a random, threedimensional diffusion process [6][7][8][9]. The mechanism utilized by DNA-targeting proteins is extremely important in determining the ability of the protein to properly interact with its target sites on DNA and, for many of these proteins, a processive mechanism of action is essential [6,8] We have previously shown that during repair of UVC light induced cyclobutane pyrimidine dimers in normal human cells, the endonucleases, XPG and XPF, incise DNA at sites of damage using a processive mechanism of action [4,5]. In contrast, these endonucleases in cells from

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Section: Introductionmentioning

confidence: 96%

Domains in the XPA protein important in its role as a processivity factor

Bartels

Lambert

2007

Biochemical and Biophysical Research Communications

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“…In higher eukaryotes, this sequential reaction is initiated by a versatile DNA damage sensor composed of XPC, Rad23B and centrin-2 [12,13]. XPC is the actual sensor subunit of this initiator complex, whereas Rad23B and centrin-2 exert accessory functions (see section 3).…”

Section: Introductionmentioning

confidence: 99%

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

Clement

Camenisch

Jia

et al. 2010

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…13 The XPC-HR23B complex functions as an early damage detector and a molecular matchmaker for recruitment of other components of the repair apparatus to the damaged DNA in global genomic NER. 14,15 Mice defective in the XPC gene are highly prone to skin cancer following exposure to UV radiation and highly vulnerable to cancers of the internal organs, such as liver and lung, when exposed to chemical carcinogens, 16,17 suggesting that XPC is important for preventing carcinogenesis. Several polymorphisms in the XPC gene have been reported [18][19][20][21] and listed in public databases (e.g., http://www.ncbi.nlm.nih.gov/ SNP).…”

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confidence: 99%

XPC polymorphisms and lung cancer risk

Lee

Jang

Lee

et al. 2005

Intl Journal of Cancer

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Polymorphisms in DNA repair genes may be associated with differences in the capacity to repair DNA damage and thereby influence an individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of 7 XPC polymorphisms (-449G?C, -371G?A, -27G?C, Val499-Arg, PAT-/+, IVS11-5C?A and Lys939Gln) and their haplotypes with lung cancer risk in a Korean population. XPC genotypes were determined in 432 lung cancer patients and 432 healthy controls frequency-matched for age and sex. XPC haplotypes were predicted using a Bayesian algorithm in the Phase program. The combined -27CGþCC genotype was associated with a significantly increased risk for overall lung cancer compared to the -27GG genotype (adjusted OR = 1.97, 95% CI 1.22-3.17, p = 0.005). The other 6 polymorphisms were not significantly associated with overall risk of lung cancer. When lung cancer cases were categorized by tumor histology, the -371AA genotype was associated with a significantly increased risk of squamous cell carcinoma compared to the combined -371GG and GA genotype (adjusted OR = 2.08, 95% CI 1.09-4.00, p = 0.03). The PAT-/+, IVS11-5C?A and Lys939Gln polymorphisms were associated with a significantly decreased risk of small cell carcinoma (SM) under a dominant model for the polymorphic allele (adjusted OR = 0.49, 95% CI 0.29-0.82, p = 0.006; adjusted OR = 0.60, 95% CI 0.36-1.00, p = 0.05; and adjusted OR = 0.58, 95% CI 0.35-0.97, p = 0.04, respectively). Consistent with genotyping analyses, haplotype 4 (1112222) containing the PAT+/IVS11-5A/939Gln alleles was associated with a significantly decreased risk of SM (adjusted OR = 0.56, 95% CI 0.37-0.85, p = 0.007 and Bonferroni-corrected p = 0.049), whereas haplotype 5 (1122111) containing the -27C allele was associated with a significantly increased risk of SM (adjusted OR = 2.88, 95% CI 1.41-5.87, p = 0.004 and Bonferronicorrected p = 0.028). These results suggest that XPC polymorphisms/haplotypes may contribute to genetic susceptibility for lung cancer. ' 2005 Wiley-Liss, Inc.

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Xeroderma Pigmentosum Group C Protein Complex Is the Initiator of Global Genome Nucleotide Excision Repair

Cited by 795 publications

References 41 publications

Domains in the XPA protein important in its role as a processivity factor

Domains in the XPA protein important in its role as a processivity factor

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

XPC polymorphisms and lung cancer risk

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