CpG islands in vertebrate genomes.

DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSalpha and MutLalpha, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.

/pdf/mechanisms-and-functions-of-dna-mismatch-repair-11cevavj74.pdf

Mechanisms and functions of DNA mismatch repair

https://www.cell.com/cell/pdf/0092-8674(87)90151-6.pdf

Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene

INTRODUCTION 339 STRUCTURAL FEATURES OF TERMINATION SITES . ......... 340 Prokaryotes ...... ..... .... ...... 341 Eukaryotes 346 FACTORS THAT REGULATE TERMINATION EFFI CIENCY AND LOCATION.... 350 Prokaryotes . . . . . . . . . . . . .. ... . . .. . . . . ... . . ... .. . . . . .. . . . . . . .. . . .. . . .. . ... . . . . . . . ......... 350 Eukaryotes 356 MECHANISTIC AND STRUCTURAL CONSIDERATIONS...... . . . ........ 359 The Dynamics of Terminati on 359 Mechanisms: Similarities and Diff erences ........ . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . 361 SUMMARY, CONCLUSIONS, AND QUE STIONS FOR THE FUTURE 363

Transcription Termination and the Regulation of Gene Expression

The c-myc gene product is a nuclear protein1,2 expressed in a wide variety of cell types3. It has been implicated in the control of normal cell growth as well as transformation4–7, but its exact function is unknown. When the human promyelocytic leukaemia cell line HL60 is treated with retinoic acid, the cells differentiate into granulocytes, and there is a reduction in steady state c-myc RNA of more than 10-fold8. Nuclear runoff assays show that this reduction is caused by a corresponding decrease in the transcription of exon 2. However, only a minor decrease in exon 1 transcription is observed upon differentiation. In undifferentiated HL60 cells there is an approximately 3-fold molar excess of exon 1 transcription over exon 2, and this excess increases to about 15-fold in differentiated cells. This observation suggests that a major component of c-myc transcriptional down-regulation in HL60 cells is at the level of elongation rather than at the level of initiation. The position of the elongation block was mapped to the region of the boundary between exon 1 and intron 1. During HL60 differentiation, a DNase I hypersensitive site in the chromatin about 300 bases downstream of the 5′ end of of intron 1 increases in intensity relative to other sites, possibly reflecting events associated with the termination of transcription. Our runoff analysis also revealed transcription of both strands immediately upstream of exon 1 in HL60 cells. The sense strand transcription of this region produces a novel c-myc RNA which initiates several hundred bases upstream of the previously defined promoters and is found in a variety of cell types.

A block to elongation is largely responsible for decreased transcription of c-myc in differentiated HL60 cells.

The use of murine dihydrofolate reductase (dhfr) gene amplification mutants enabled us to identify important structural and functional features of the dhfr promoter region. We found another transcription unit, at least 14 kilobases in size, which initiates within 130 base pairs of the major dhfr transcript and is transcribed divergently. The 5' ends of both transcripts were analyzed and found to have multiple initiation sites. The major dhfr transcript and the divergent transcript appear to share the same promoter region; the longer transcripts of the dhfr gene overlap with the divergent transcripts and use a different promoter region. The divergent transcript appears to code for a protein; an homologous sequence to its first exon is found in the corresponding location near the human dhfr gene.

Analysis of the mouse dhfr promoter region: existence of a divergently transcribed gene.

Theuseofmurine dihydrofolate reductase (dhfr) geneamplification mutants enabled ustoidentify important structural andfunctional features ofthedhfr promoter region. We foundanother transcription unit, atleast 14kilobases insize, whichinitiates within 130basepairs ofthemajor dhfrtranscript andistranscribed divergently. The5'endsofbothtranscripts wereanalyzed andfoundtohavemultiple initiation sites. The major dhfrtranscript andthedivergent transcript appear toshare thesamepromoter region; thelonger transcripts ofthedhfr geneoverlap withthedivergent transcripts anduseadifferent promoter region. The divergent transcript appears tocodeforaprotein; anhomologous sequence toitsfirst exonisfoundinthe corresponding location nearthehumandhfr gene. Mostcellular generegulation studies havebeenconcerned with genes that codeforproteins produced inlarge quantities inspecific typesofterminally differentiated cells. A large bodyofevidence indicates that theexpression ofsuchgenes iscontrolled transcriptionally (10). However, manycellular genes, perhaps most, codeforenzymes which arepresent at lowlevels invirtually all types ofcells. Studies concerning theexpression ofhousekeeping enzymes orproteins suchas dihydrofolate reductase (dhfr; 17,20,21), thymidine kinase (15), tubulin (7,16), andglyceraldehyde-3-phosphate dehydrogenase (29)indicate thatthedifferential expression of these genesseenasafunction ofcell growth orseenin different tissues iscontrolled posttranscriptionally. Thus,

Analysis oftheMousedhfr Promoter Region: Existence ofa Divergently Transcribed Gene

We observed equimolar transcription throughout the 35-kilobase mouse dihydrofolate reductase structural gene. Transcription termination occurred within a discrete region (900 base pairs) located 1 kilobase beyond the last of seven functional polyadenylation sites and near a repetitive DNA sequence element. The results imply that a distinct genetic signal may be associated with the process of transcription termination.

Transcription of the mouse dihydrofolate reductase gene proceeds unabated through seven polyadenylation sites and terminates near a region of repeated DNA.

The mouse dihydrofolate reductase gene (dhfr) is a housekeeping gene expressed under the control of a promoter region embedded in a CpG island--a region rich in unmethylated CpG dinucleotides. A divergent transcription unit exists immediately upstream of the dhfr gene which is coamplified with dhfr in some but not all methotrexate-resistant cell lines. We show that the promoter region for this gene pair consists of two bidirectional promoters, a major and minor promoter, which are situated within a 660-base-pair region upstream of the dhfr ATG translation initiation codon. The major promoter controls over 90% of dhfr transcription, while the minor promoter directs the transcription of the remaining dhfr mRNAs. The major promoter functions bidirectionally, transcribing a divergent 4.0-kilobase poly(A) mRNA (class A) in the direction opposite that of dhfr transcription. The predicted protein product of this mRNA is 105 kilodaltons. The minor promoter also functions bidirectionally, directing the transcription of at least two divergent RNAs (class B). These RNAs, present in quantities approximately 1/10 to 1/50 that of the class A mRNAs, are 4.4- and 1.6-kilobase poly(A) mRNAs. cDNAs representing both class A and class B mRNAs have been cloned from a mouse fibroblast cell line which has amplified the dhfr locus (3T3R500). DNA sequence analysis of these cDNAs reveals that the class A and class B mRNAs share, for the most part, the same exons. On the basis of S1 nuclease protection analysis of RNA preparations from several mouse tissues, both dhfr and divergent genes showed similar levels of expression but did show some specificity in start site utilization. Computer homology searches have revealed sequence similarity of the divergent transcripts with bacterial genes involved in DNA mismatch repair, and we therefore have named the divergently transcribed gene Rep-1.

Dual bidirectional promoters at the mouse dhfr locus: cloning and characterization of two mRNA classes of the divergently transcribed Rep-1 gene.

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Analysis of the mouse dhfr promoter region: existence of a divergently transcribed gene.

Analysis oftheMousedhfr Promoter Region: Existence ofa Divergently Transcribed Gene

Transcription of the mouse dihydrofolate reductase gene proceeds unabated through seven polyadenylation sites and terminates near a region of repeated DNA.

Dual bidirectional promoters at the mouse dhfr locus: cloning and characterization of two mRNA classes of the divergently transcribed Rep-1 gene.