Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

My colleagues and I have discovered intragenomic heterogeneity in DNA repair in mammalian cells. Consequences of unrepaired DNA damage depend upon the precise location of the damage with respect to relevant genes. It is therefore important to understand rules governing accessibility of specific DNA sequences in chromatin to damage and repair. The efficiency of removal of pyrimidine dimers has been mapped in the active dihydrofolate reductase (DHFR) gene in Chinese hamster ovary (CHO) cells. Repair within the gene was shown to be much more efficient than that in silent downstream sequences or in the genome overall. Preferential repair of active and essential genes such as DHFR may account for the fact that rodent cells are as UV-resistant as human cells in spite of their much lower overall repair efficiencies. In repair proficient human cells the rate of repair in the DHFR gene is greater than that in the overall genome or in non-transcribed alpha DNA sequences. The efficiency of removal of pyrimidine dimers is much higher in the transcribed than the non-transcribed DNA strands of the DHFR gene in both CHO and human cells. An excision-repair complex may be directly coupled to the transcription machinery to ensure early removal of transcription-blocking lesions in active genes. Sequences in the active c-abl protooncogene are repaired much more efficiently than are sequences containing the inactive c-mos protooncogene in Swiss mouse 3T3 cells. Tissue specific and cell specific differences in the coordinate regulation of protooncogene expression and DNA repair may account for corresponding differences in the carcinogenic response. Efficient replicative bypass of persisting psoralen monoadducts, but not interstrand crosslinks, was demonstrated in the human DHFR gene. It is likely that most bulky lesions in mammalina DNA, other than crosslinks, do not pose insurmountable problems for replication in vivo, but they must be removed from essential transcribed sequences to maintain cellular viability.
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PMID:Selective DNA repair in active genes. 209 32

My colleagues and I have discovered intragenomic heterogeneity in DNA repair in mammalian cells. Consequences of unrepaired DNA damage depend upon the precise location of the damage with respect to relevant genes. It is therefore important to understand rules governing accessibility of specific DNA sequences in chromatin to damage and repair. The efficiency of removal of pyrimidine dimers has been determined in the active dihydrofolate reductase (DHFR) gene in Chinese hamster ovary (CHO) cells. Repair within the gene was shown to be much more efficient than that in nontranscribed downstream sequences or in the genome overall. Preferential repair of active and essential genes such as DHFR may account for the fact that rodent cells are as uv-resistant as human cells in spite of their much lower overall repair efficiencies. In repair-proficient human cells the rate of repair in the DHFR gene is greater than that in the overall genome or in nontranscribed alpha-DNA sequences. The efficiency of removal of pyrimidine dimers is much higher in the transcribed than the nontranscribed DNA strands of the DHFR gene in both CHO and human cells. An excision-repair complex may be directly coupled to the transcription machinery to ensure early removal of transcription-blocking lesions in active genes. Sequences in the active c-abl proto-oncogene are repaired much more efficiently than are sequences containing the inactive c-mos proto-oncogene in Swiss mouse 3T3 cells. Tissue-specific and cell-specific differences in the coordinate regulation of proto-oncogene expression and DNA repair may account for corresponding differences in the carcinogenic response.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Preferential repair of damage in actively transcribed DNA sequences in vivo. 269 35

To investigate the influence of function or activity of a DNA sequence on its repair, we have studied excision repair of a number of adducts in the non-transcribed, heterochromatic alpha DNA of monkey cells (by physically isolating the DNA) and also the removal of pyrimidine dimers in a number of genes in rodent and human cells (by an indirect assay using a dimer-specific endonuclease). In confluent cells, psoralen and aflatoxin B1 (AFB1) adducts are produced in similar frequencies in alpha and in the rest of the DNA, but removal from alpha is severely deficient. Adducts of N-acetoxyacetylaminofluorene (NA-AAF) are formed in slightly higher frequencies in alpha, and removal is slightly deficient. The removal of thymine glycols from alpha DNA in gamma-irradiated cells is proficient, as is repair synthesis elicited by exposure to methyl methane sulphonate, dimethyl sulphate, or 254 nm ultraviolet light (u.v.). Removal of AFB1 and NA-AAF adducts from alpha is enhanced by small doses of u.v. but not by X-rays or DMS. The quantum efficiency of conversion of psoralen monoadducts to crosslinks is much lower in alpha DNA. Taken together, these results suggest that the highly condensed chromatin structure of alpha hinders access of the repair system that acts on bulky adducts but not of systems for repair of specific base damage, u.v. damage may alter this chromatin structure directly or facilitate the action of some system that changes accessibility of chromatin to repair. The repair deficiencies are not observed in actively growing cells, in which chromatin structure may be less condensed due to DNA replication. We have also demonstrated preferential excision repair of pyrimidine dimers in active genes. Dimers are efficiently removed from the essential dihydrofolate reductase (DHFR) and hydroxymethylglutaryl CoA reductase genes in Chinese hamster ovary (CHO) cells and from the transcribed c-ab1 proto-oncogene in the mouse cells. Both cell types remove few dimers from their overall genomes or from sequences distal to the DHFR gene; dimers are also removed poorly from the non-transcribed mouse c-mos gene. In human cells, dimers are removed more rapidly from the DHFR gene than from the genome as a whole. However, repair is as deficient in this gene in XP-C cells as it is in the entire genome. These results suggest that resistance to DNA damage correlates better with repair of vital or active sequences than with overall repair levels and that mutagenic efficiency may vary according to the activity of the gene under study.
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PMID:DNA repair in specific sequences in mammalian cells. 311 98

The product of the c-mos proto-oncogene is a protein kinase that is normally expressed in germ cells and functions during oocyte maturation. It has been shown, however, that inappropriate expression of either the viral or cellular mos gene can induce neoplastic progression in somatic cells. Furthermore, v-mos-transformed NIH3T3 cells will undergo arrest of proliferation in early G1 upon serum withdrawal but are unable to appropriately down-regulate cell cycle regulatory proteins, such as cyclin and cdc2 proteins, that normally are down-regulated in quiescent, untransformed NIH3T3 cells. Since the levels of these proteins are partially transcriptionally controlled, we investigated whether there were alterations in the expression of E2F and AP-1 transcription factor complexes. Indeed, the putative G0/G1-specific p130-E2F complex that is normally observed during low serum-induced cell cycle arrest in NIH3T3 cells is not present in serum starved v-mos-transformed cells. Instead, G1-phase arrested v-mos-transformed cells stably express two E2F protein complexes that are normally observed only during S-phase in untransformed cells. The elevation of these complexes in arrested v-mos-transformed cells may be the cause of the transcriptional activation of the E2F-regulated genes cdc2, DHFR, cyclin A, and E2F1 seen in serum starved v-mos-transformed cells. In addition, there are high levels of AP-1 DNA binding activity in serum starved v-mos-transformed cells compared to very low amounts in nontransformed cells. This altered regulation of transcription factor complexes and cell cycle control proteins upon serum withdrawal may provide a mechanism for the uncontrolled cell growth associated with neoplastic transformation induced by certain proto-oncogenes.
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PMID:Deregulation of specific E2F complexes by the v-mos oncogene. 922 66