Structure–Function Correlations of the Insulin-linked Polymorphic Region

Catasti, P.; Chen, Xian; Moyzis, Robert K.; Bradbury, E. M.; Gupta, Goutam

doi:10.1006/jmbi.1996.0659

Cited by 138 publications

(126 citation statements)

References 34 publications

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“…Based on our knowledge that the G-rich strand of MN Pc-1 and other short tandem repeats such as d(CGG) n triplet repeat and insulin-variable number of tandem repeat fold into a quadruplex structure and causes the arrest of DNA synthesis in vitro, the characteristic structure of the repeats could be responsible for the hypermutable feature of Pc-1 and other tandem repeats with similar repetitive units (15,40,41). In the case of d(CGG) n triplet repeat, WRN helicase was demonstrated to facilitate copying of the quadruplex structure of the triplet repeat by DNA polymerase ␦ in vitro (42).…”

Section: Discussionmentioning

confidence: 99%

Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1

Fukuda

Katahira

Tsuchiya

et al. 2002

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

104

102

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The mouse hypervariable minisatellite (MN) Pc-1 consists of tandem repeats of d(GGCAG) and flanked sequences. We have previously demonstrated that single-stranded d(GGCAG)n folds into the intramolecular folded-back quadruplex structure under physiological conditions. Because DNA polymerase progression in vitro is blocked at the repeat, the characteristic intramolecular quadruplex structure of the repeat, at least in part, could be responsible M inisatellites (MNs), also called variable number of tandem repeats, are arrays of 5-to 100-bp repeats widely dispersed in eukaryotic genomes (1). Some have been suggested to be implicated in genetic predisposition to various human diseases. Although MNs are known to be hot spots for meiotic recombination in germ cells (1, 2), they are considered to be genetically stable in somatic cells (3). However, they also have been demonstrated to be altered in somatic cells with exposure to chemical carcinogens, ␥ irradiation, or UV irradiation (4-7). They also exhibit alterations in a range of tumors of humans and experimental animals (8-10).The MN Pc-1, located on mouse chromosome 4, consists of tandem repeats of d(GGCAG) (11, 12). The germ-line mutation rate for Pc-1 is 15% per gamete, whereas the mutation rate in somatic cells is 2-3% per 22-24 population doublings (12-14). Many hypervariable MNs, consisting of G-rich repeat units similar to Pc-1, have been found in the mouse and other mammalian genomes, and mouse MNs containing d(GGCAG) n or d(GGCAGG) n motifs are very unstable in germ-line cells (11). Pc-1 and Pc-1-like MNs were demonstrated to be strikingly unstable by DNA fingerprint analysis, both in fibroblasts deficient in DNA-dependent protein kinase activity and in NIH 3T3 cells treated with okadaic acid, an inhibitor of protein phosphatases (13,14).Although the molecular mechanisms underlying the induction of MN mutations are largely unknown, the G-rich strand of Pc-1 is known to form an intramolecular folded-back quadruplex structure under physiological conditions and cause arrest of DNA synthesis (15). We have isolated six MN Pc-1 binding proteins (MNBPs) from NIH 3T3 cells (16). Two of them, MNBP-A and MNBP-B, bind to the G-rich strand of Pc-1, and the other four, MNBP-D, MNBP-E, MNBP-F, and MNBP-G, to the complementary C-rich strand.In this article, we document isolation of cDNA clones encoding MNBP-B and characterization of a recombinant MNBP-B. Sequences of seven proteolytic peptides of purified MNBP-B were determined, and cDNA clones were subsequently isolated. MNBP-B was revealed to be identical to the single-stranded DNA binding protein, UP1 (17), which is a proteolytic product corresponding to the N-terminal 195 aa of the 34-kDa heterogeneous nuclear ribonucleoprotein (hnRNP) A1 (18, 19). DNA binding specificity and in vitro effect on quadruplex structures of UP1 were analyzed to cast light on its biological roles. EMSA. EMSA and analyses of oligonucleotide competition using EMSA were performed as detailed (16) with 32 P-labeled pG8 (final concentration 2 nM)...

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Section: Discussionmentioning

confidence: 99%

Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1

Fukuda

Katahira

Tsuchiya

et al. 2002

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

104

102

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“…Since for most but not all repeats activation by Pur-1 correlated with Pur-1 binding activity in vitro, other factors that recognize the G-quartet structure are likely to be involved in transcriptional regulation of the gene [88]. Indeed, single or double mutations that destabilise the loop-loop and loop-tetrad interactions dramatically affected insulin promoter activity [90].…”

Section: Ilpr (Vntr Hvr)mentioning

confidence: 99%

Regulation of insulin gene transcription

2002

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Insulin, synthesized by the beta cells of pancreatic islets, is of major physiological importance in metabolic homeostasis. While mature insulin consists of two polypeptide chains joined by disulphide bridges, the gene encodes for a highly conserved single chain precursor, preproinsulin [1]. In most species preproinsulin exists as a single gene, whereas in the mouse and the rat two non-allelic insulin genes are present. The human insulin gene is located on the short arm of chromosome 11 (p15.5) [2], the rat insulin I and II genes are colocalized on chromosome 1 [3] and the mouse genes are positioned on two different chromosomes, insulin I on chromosome 19 [4] and insulin II on chromosome 7 [5]. In adult islets, the nonallelic genes appear to be coordinately expressed and regulated [6, 7]. The rodent insulin II and the human genes contain three exons and two introns, whilst insulin I lacks the second intron. The organisation and structure of the insulin gene has been reviewed in detail [8]. Insulin is regulat- AbstractThe mammalian insulin gene is exclusively expressed in the beta cells of the endocrine pancreas. Two decades of intensive physiological and biochemical studies have led to the identification of regulatory sequence motifs along the insulin promoter and to the isolation of transcription factors which interact to activate gene transcription. The majority of the islet-restricted (BETA2, PDX-1, RIP3b1-Act/C1) and ubiquitous (E2A, HEB) insulin-binding proteins have been characterized. Transcriptional regulation results not only from specific combinations of these activators through DNA-protein and protein-protein interactions, but also from their relative nuclear concentrations, generating a cooperativity and transcriptional synergism unique to the insulin gene. Their DNA binding activity and their transactivating potency can be modified in response to nutrients (glucose, NEFA) or hormonal stimuli (insulin, leptin, glucagon like peptide-1, growth hormone, prolactin) through kinase-dependent signalling pathways (PI3-K, p38MAPK, PKA, CaMK) modulating their affinities for DNA and/or for each other. From the overview of the research presented, it is clear that much more study is required to fully comprehend the mechanisms involved in the regulated-expression of the insulin gene in the beta cell to prevent its impairment in diabetes. [Diabetologia (2002) 45: 309±326]

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“…Despite intensive effort, the cause of the association with the insulin gene region is still not known. It is possible that the VNTR itself directly influences insulin gene expression [103,104]. However, some studies showed high-risk, short alleles to be associated with increased insulin gene transcription in the pancreas [105,106], while another study showed protective long alleles to be associated with increased transcription [107].…”

Section: The Challenges Of Searching For Type I Diabetes Genesmentioning

confidence: 99%

Genetic linkage and association studies of Type I diabetes: challenges and rewards

Field

2002

Diabetologia

104

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Type I diabetes (formerly called insulin-dependent diabetes mellitus) results from the autoimmune destruction of the insulin-producing beta cells of the pancreas. It is now known that Type I diabetes is a genetically complex disease, i. e. a disease caused by multiple genes interacting with non-genetic (environmental and stochastic) factors. Family studies have clearly shown a genetic basis but inheritance of the disease does not follow a simple mendelian single-locus pattern. Population and family studies also suggest that most (perhaps all) affected individuals are genetically predisposed to Type I diabetes, particularly through HLA region genes. However, non-genetic factors appear to be required to precipitate the disease in these genetically susceptible persons because in monozygote (MZ) twin pairs in which one twin has Type I diabetes the MZ twin concordance rate is less than 100 %. It is not clear whether there are any purely genetic cases of Type I Diabetologia (2002) AbstractFamily and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies. [Diabetologia (2002) 45: 21±35]

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Structure–Function Correlations of the Insulin-linked Polymorphic Region

Cited by 138 publications

References 34 publications

Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1

Unfolding of quadruplex structure in the G-rich strand of the minisatellite repeat by the binding protein UP1

Regulation of insulin gene transcription

Genetic linkage and association studies of Type I diabetes: challenges and rewards

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