Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043346 (xeroderma pigmentosum)
 2,924 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xeroderma pigmentosum (XP) patients are extremely sensitive to ultraviolet (UV) light and suffer from a high incidence of skin cancers, due to a defect in nucleotide excision repair. The disease is genetically heterogeneous, and seven complementation groups, A-G, have been identified. Homologs of human excision repair genes ERCC1, XPDC/ERCC2, and XPAC have been identified in the yeast Saccharomyces cerevisiae. Since no homolog of human XPBC/ERCC3 existed among the known yeast genes, we cloned the yeast homolog by using XPBC cDNA as a hybridization probe. The yeast homolog, RAD25 (SSL2), encodes a protein of 843 amino acids (M(r) 95,356). The RAD25 (SSL2)- and XPBC-encoded proteins share 55% identical and 72% conserved amino acid residues, and the two proteins resemble one another in containing the conserved DNA helicase sequence motifs. A nonsense mutation at codon 799 that deletes the 45 C-terminal amino acid residues in RAD25 (SSL2) confers UV sensitivity. This mutation shows epistasis with genes in the excision repair group, whereas a synergistic increase in UV sensitivity occurs when it is combined with mutations in genes in other DNA repair pathways, indicating that RAD25 (SSL2) functions in excision repair but not in other repair pathways. We also show that RAD25 (SSL2) is an essential gene. A mutation of the Lys392 residue to arginine in the conserved Walker type A nucleotide-binding motif is lethal, suggesting an essential role of the putative RAD25 (SSL2) ATPase/DNA helicase activity in viability.
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PMID:RAD25 (SSL2), the yeast homolog of the human xeroderma pigmentosum group B DNA repair gene, is essential for viability. 133 9

The SSL1 locus was identified as a trans-acting suppressor that restores HIS4 expression despite a stem-loop structure in the 5'-UTR. SSL1 encodes an essential protein of 52 kD with features characteristic of a protein with multiple zinc fingers. The mechanism of SSL1 suppression is not related to altering his4 transcription or removing the stem-loop sequence from the 5'-UTR; rather, 3- to 5-fold increases in His4 translational expression are observed indicating a post-transcriptional mechanism for SSL1 suppression. SSL1 suppressor mutants that are conditional for growth have altered polysome profiles at the restrictive temperature, and their cell-free extracts are thermolabile in their ability to translate exogenously added mRNA. In addition, the mechanism of suppression appears to be specific for stem-loop structures placed near the 5' end of the message as opposed to a stem-loop located at a downstream position in the 5'-UTR. These observations suggest a role for this protein in promoting translation initiation presumably at the level of ribosomal binding to mRNA. Surprisingly, SSL1 suppressor mutations that are shown to confer an in vivo and in vitro defect in translation initiation also rendered yeast hypersensitive to UV irradiation. This latter phenotype was observed previously with a mutation in the SSL2 suppressor gene, which encodes the yeast homolog of the human gene ERCC-3, for which a defective form causes xeroderma pigmentosum. In light of the related effects of mutations in the SSL1 and SSL2 genes, the encoded proteins may functionally interact both to promote DNA repair and perform an essential function during translation initiation.
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PMID:SSL1, a suppressor of a HIS4 5'-UTR stem-loop mutation, is essential for translation initiation and affects UV resistance in yeast. 134 Apr 63

The mouse XPG gene is a homolog of the human DNA excision repair gene known to be defective in the hereditary sun-sensitive disorder xeroderma pigmentosum (group-G). Defects in mouse XPG have been shown to directly affect the sensitivity of cultured cells to chemotherapy agents and may play a role in tumor cell drug resistance in vivo. A full-length cosmid clone of mouse XPG was isolated by complementation of the UV sensitivity and repair defect in CHO-UV135 cells. Exon mapping determined that the gene consisted of 15 exons within 32 kb of genomic DNA. Sequencing of intron-exon boundaries revealed that mouse XPG possesses a rare class of intron previously identified in only four other eukaryotic genes; it utilizes AT and AC dinucleotides instead of the expected GT and AG within the splice junctions. Promoter analysis determined that mouse XPG is expressed constitutively and probably initiates transcription from multiple start sites, yet, unlike the yeast homolog RAD2, we found no evidence that it is UVC inducible in cultured cells. Amino acid comparison with human XPG identified a highly conserved acidic region of homology not previously described.
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PMID:Molecular cloning and structural analysis of the functional mouse genomic XPG gene. 870 15

The Xeroderma pigmentosum complementation group C (XPC) complex is a versatile factor involved in both nucleotide excision repair and transcriptional coactivation as a critical component of the NANOG, OCT4, and SOX2 pluripotency gene regulatory network. Here we present the structure of the human holo-XPC complex determined by single-particle electron microscopy to reveal a flexible, ear-shaped structure that undergoes localized loss of order upon DNA binding. We also determined the structure of the complete yeast homolog Rad4 holo-complex to find a similar overall architecture to the human complex, consistent with their shared DNA repair functions. Localized differences between these structures reflect an intriguing phylogenetic divergence in transcriptional capabilities that we present here. Having positioned the constituent subunits by tagging and deletion, we propose a model of key interaction interfaces that reveals the structural basis for this difference in functional conservation. Together, our findings establish a framework for understanding the structure-function relationships of the XPC complex in the interplay between transcription and DNA repair.
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PMID:Architecture of the human XPC DNA repair and stem cell coactivator complex. 2662 36