Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic and biochemical studies of Saccharomyces cerevisiae have indicated the involvement of a large number of protein factors in nucleotide excision repair (NER) of UV-damaged DNA. However, how MMS19 affects this process has remained unclear. Here, we report on the isolation of the MMS19 gene and the determination of its role in NER and other cellular processes. Genetic and biochemical evidence indicates that besides its function in NER, MMS19 also affects RNA polymerase II (Pol II) transcription. mms19delta cells do not grow at 37 degrees C, and mutant extract exhibits a thermolabile defect in Pol II transcription. Thus, Mms19 protein resembles TFIIH in that it is required for both transcription and DNA repair. However, addition of purified Mms19 protein does not alleviate the transcriptional defect of the mms19delta extract, nor does it stimulate the incision of UV-damaged DNA reconstituted from purified proteins. Interestingly, addition of purified TFIIH corrects the transcriptional defect of the mms19delta extract. Mms19 is, however, not a component of TFIIH or of Pol II holoenzyme. These and other results suggest that Mms19 affects NER and transcription by influencing the activity of TFIIH as an upstream regulatory element. It is proposed that mutations in the human MMS19 counterpart could result in syndromes in which both NER and transcription are affected.
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PMID:Dual requirement for the yeast MMS19 gene in DNA repair and RNA polymerase II transcription. 894 33

The MMS19 gene of the yeast Saccharomyces cerevisiae encodes a polypeptide of unknown function which is required for both nucleotide excision repair (NER) and RNA polymerase II (RNAP II) transcription. Here we report the molecular cloning of human and mouse orthologs of the yeast MMS19 gene. Both human and Drosophila MMS19 cDNAs correct thermosensitive growth and sensitivity to killing by UV radiation in a yeast mutant deleted for the MMS19 gene, indicating functional conservation between the yeast and mammalian gene products. Alignment of the translated sequences of MMS19 from multiple eukaryotes, including mouse and human, revealed the presence of several conserved regions, including a HEAT repeat domain near the C-terminus. The presence of HEAT repeats, coupled with functional complementation of yeast mutant phenotypes by the orthologous protein from higher eukaryotes, suggests a role of Mms19 protein in the assembly of a multiprotein complex(es) required for NER and RNAP II transcription. Both the mouse and human genes are ubiquitously expressed as multiple transcripts, some of which appear to derive from alternative splicing. The ratio of different transcripts varies in several different tissue types.
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PMID:Cloning the human and mouse MMS19 genes and functional complementation of a yeast mms19 deletion mutant. 1132 71

Nucleotide excision repair (NER) and RNA polymerase II (Pol II) transcription are essential cellular processes which are intimately intertwined. They share an indispensable multiprotein complex, TFIIH, and impairments in either process can impact the efficiency of the other. Like TFIIH, MMS19 is required for NER and Pol II transcription, but its precise role in each process is unknown. We showed previously that the human MMS19 gene originates multiple splice variants, some of which may encode distinct MMS19 protein isoforms. Here we characterize a novel MMS19 transcript and demonstrate for the first time that MMS19 splice variants are conserved across species and are functionally distinct. Expression of human MMS19 splice variants in mms19-deleted yeast cells produced unique patterns of thermosensitivity and ultraviolet radiation-sensitivity that point to three MMS19 structural domains with distinct in vivo functions. MMS19 polypeptides lacking domain A are able to fulfill the role of full-length MMS19 in NER but not in transcription. MMS19 polypeptides lacking part of domain B are efficient in transcription but not in NER. MMS19 polypeptides lacking domain C (HEAT repeats) are unable to fulfill either function. Our data suggest that the MMS19 HEAT repeat domain is essential for MMS19 function in NER and transcription, while domains A and B, within MMS19 N-terminus, modulate the balance between DNA repair and transcription. Our results highlight the functional significance of MMS19 transcripts and the possible contribution of MMS19 isoforms to regulate the switch between NER and transcription. Furthermore, our work associates for the first time specific protein domains with MMS19's role in NER and transcription.
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PMID:Identification of MMS19 domains with distinct functions in NER and transcription. 1679 55