Heritable genetic alterations in a xeroderma pigmentosum group G/Cockayne syndrome pedigree

Okinaka, Richard T.; Perez-Castro, Ana V.; Sena, Anthony P.; Laubscher, Kevin; Strniste, G.F.; Park, Min S; Hernandez, R R; MacInnes, Mark A.; Kraemer, Kenneth H.

doi:10.1016/s0921-8777(97)00031-1

Cited by 29 publications

(33 citation statements)

References 31 publications

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“…The most susceptible fibroblasts come from XP20BE, an XP-G/CS boy, who encoded severely truncated XPG proteins of 10 and 137 amino acids, compared to full-length XPG of 1186 amino acids 30 (and A Pigni, unpublished). The other XP-G/CS cells examined are from XPCS2RO who made a protein of 980 amino acids from both XPG alleles (F Thorel, unpublished).…”

Section: Discussion Apoptosis In Xpg-deficient Fibroblastsmentioning

confidence: 99%

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Clément¹,

Dunand-Sauthier²,

Sg³

2005

Cell Death Differ

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The severe xeroderma pigmentosum/Cockayne syndrome (XP/CS) syndrome is caused by mutations in the XPB, XPD and XPG genes that encode the helicase subunits of TFIIH and the 3 0 endonuclease of nucleotide excision repair (NER). Because XPB and XPD have been implicated in p53-mediated apoptosis, we examined the possible involvement of XPG in this process. After ultraviolet light (UV) irradiation, primary fibroblasts of XP complementation group G (XP-G) individuals with CS enter apoptosis more readily than other NER-deficient cells, but this is unlinked to unrepaired damage. These XP-G/ CS cells accumulate p53 post-UV but they fail to accumulate the 90/92 kDa isoforms of Mdm2 and their cellular distribution of Mdm2 is impaired. Apoptosis levels revert to wild type, Mdm2 90/92 kDa isoforms accumulate, and Mdm2 regains its normal post-UV nuclear location in transduced XP-G/CS cells expressing wild-type XPG, but not an XPG catalytic site mutant. These results suggest that XPG suppresses UVinduced apoptosis and that this suppression, most simply, requires its endonuclease function.

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Section: Discussion Apoptosis In Xpg-deficient Fibroblastsmentioning

confidence: 99%

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Clément¹,

Dunand-Sauthier²,

Sg³

2005

Cell Death Differ

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“…Nonproliferating fibroblasts defective in either XPF or XPG nucleases (22,23) are unable to phosphorylate Chk1 and p53 after UV irradiation (Fig. 4A).…”

Section: Open Complex Formation and Processing Of The Lesion Are Necementioning

confidence: 98%

DNA nucleotide excision repair-dependent signaling to checkpoint activation

Marini

Nardò

Giannattasio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

112

102

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“…For the transduction experiments, primary fibroblasts from a severely affected XP-G/CS patient (XP20BE) (45,46) were cultured in modified Eagle's medium supplemented with 15% fetal calf serum, 2 mM L-glutamine, 100 units/ml penicillin, and 100 g/ml streptomycin. Cells were kept in a 5% CO 2 humidified incubator.…”

Section: Construction Of Xpg Spacer Deletion Mutants-deletion Mutantsmentioning

confidence: 99%

The Spacer Region of XPG Mediates Recruitment to Nucleotide Excision Repair Complexes and Determines Substrate Specificity

Dunand-Sauthier

Hohl

Thorel

et al. 2005

Journal of Biological Chemistry

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XPG has structural and catalytic roles in nucleotide excision repair (NER) and belongs to the FEN-1 family of structure-specific nucleases. XPG contains a stretch of over 600 amino acids termed the "spacer region" between the conserved N-and I-nuclease regions. Its role is unknown, and it is not similar to any known protein. To investigate its possible functions, we generated and analyzed several deletion mutants of XPG. The spacer region is not required for endonuclease activity, but amino acids 111-550 contribute to the substrate specificity of XPG, and they are required for interaction with TFIIH and for NER activity in vitro and in vivo. Deletion of residues 184 -210 and 554 -730 leads only to a partial defect in NER activity and a weakened interaction with TFIIH. XPG⌬184 -210 and XPG⌬554 -730 are not observed at sites of local UV damage in living cells by immunofluorescence, suggesting that the weakened interaction between XPG and TFIIH results in an NER reaction with altered kinetics. This study demonstrates that the N-terminal portion of the spacer region is particularly important for NER progression by mediating the XPG-TFIIH interaction and XPG substrate specificity.

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Heritable genetic alterations in a xeroderma pigmentosum group G/Cockayne syndrome pedigree

Cited by 29 publications

References 31 publications

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

Suppression of UV-induced apoptosis by the human DNA repair protein XPG

DNA nucleotide excision repair-dependent signaling to checkpoint activation

The Spacer Region of XPG Mediates Recruitment to Nucleotide Excision Repair Complexes and Determines Substrate Specificity

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