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1.
Genes Immun ; 9(8): 721-6, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18719602

RESUMO

Mutations in NLRP3 (CIAS1) are identified in a continuum of related inflammatory disorders, known as cryopyrinopathies since NLRP3 codes for the protein cryopyrin. Approximately 40% of patients with classic presentation lack mutations in the coding region of NLRP3 suggesting heterogeneity or epigenetic factors. Cryopyrin is a key regulator of proinflammatory cytokine release. Therefore, variations in the NLRP3 promoter sequence may have effects on disease state in patients with cryopyrinopathies and other inflammatory diseases. In this report, we confirmed three 5'-untranslated region splice forms with two separate transcriptional start sites, and identified potential promoter regions and six new DNA promoter variants. One variant is unique to a mutation negative cryopyrinopathy patient and increases in vitro gene expression. Additional studies can now be performed to further characterize the NLRP3 promoter and sequence variants, which will lead to better understanding of the regulation of NLRP3 expression and its role in disease.


Assuntos
Proteínas de Transporte/genética , Regiões Promotoras Genéticas/genética , Sítios de Splice de RNA/genética , Humanos , Inflamação/genética , Leucócitos , Proteína 3 que Contém Domínio de Pirina da Família NLR
2.
Nat Genet ; 29(3): 301-5, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11687797

RESUMO

Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold. FCAS was previously mapped to a 10-cM region on chromosome 1q44 (refs. 5,6). Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present. To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls. This resulted in the identification of four distinct mutations in a gene that segregated with the disorder in three families with FCAS and one family with MWS. This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis.


Assuntos
Doenças Autoimunes/genética , Proteínas Sanguíneas/genética , Proteínas de Transporte/genética , Temperatura Baixa/efeitos adversos , Febre Familiar do Mediterrâneo/genética , Mutação de Sentido Incorreto/genética , Proteínas/química , Motivos de Aminoácidos , Sequência de Aminoácidos , Doenças Autoimunes/complicações , Sequência de Bases , Proteínas Sanguíneas/química , Proteínas de Transporte/química , Mapeamento Cromossômico , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Éxons/genética , Feminino , Perfilação da Expressão Gênica , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/genética , Humanos , Inflamação/complicações , Inflamação/genética , Íntrons/genética , Masculino , Dados de Sequência Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR , Linhagem , Estrutura Terciária de Proteína , Pirina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência do Ácido Nucleico
3.
Cancer Res ; 61(21): 7934-42, 2001 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-11691815

RESUMO

In mammalian cells, mismatch recognition has been attributed to two partially redundant heterodimeric protein complexes of MutS homologues, MSH2-MSH3 and MSH2-MSH6. We have conducted a comparative analysis of Msh3 and Msh6 deficiency in mouse intestinal tumorigenesis by generating Apc1638N mice deficient in Msh3, Msh6 or both. We have found that Apc1638N mice defective in Msh6 show reduced survival and a 6-7-fold increase in intestinal tumor multiplicity. In contrast, Msh3-deficient Apc1638N mice showed no difference in survival and intestinal tumor multiplicity as compared with Apc1638N mice. However, when Msh3 deficiency is combined with Msh6 deficiency (Msh3(-/-)Msh6(-/-)Apc1638N), the survival rate of the mice was further reduced compared to Msh6(-/-)Apc(1638N) mice because of a high multiplicity of intestinal tumors at a younger age. Almost 90% of the intestinal tumors from both Msh6(-/-)Apc1638N and Msh3(-/-)Msh6(-/-)Apc1638N mice contained truncation mutations in the wild-type Apc allele. Apc mutations in Msh6(-/-)Apc1638N mice consisted predominantly of base substitutions (93%) creating stop codons, consistent with a major role for Msh6 in the repair of base-base mismatches. However, in Msh3(-/-)Msh6(-/-)Apc1638N tumors, we observed a mixture of base substitutions (46%) and frameshifts (54%), indicating that in Msh6(-/-)Apc1638N mice frameshift mutations in the Apc gene were suppressed by Msh3. Interestingly, all except one of the Apc mutations detected in mismatch repair-deficient intestinal tumors were located upstream of the third 20-amino acid beta-catenin binding repeat and before all of the Ser-Ala-Met-Pro repeats, suggesting that there is selection for loss of multiple domains involved in beta-catenin regulation. Our analysis therefore has revealed distinct mutational spectra and clarified the roles of Msh3 and Msh6 in DNA repair and intestinal tumorigenesis.


Assuntos
Pareamento Incorreto de Bases , Reparo do DNA/fisiologia , Proteínas de Ligação a DNA/fisiologia , Genes APC/fisiologia , Neoplasias Intestinais/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Mutação , Animais , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Predisposição Genética para Doença , Endogamia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Repetições de Microssatélites/genética , Proteína 3 Homóloga a MutS
4.
Mol Cell Biol ; 21(15): 5142-55, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11438669

RESUMO

EXO1 interacts with MSH2 and MLH1 and has been proposed to be a redundant exonuclease that functions in mismatch repair (MMR). To better understand the role of EXO1 in mismatch repair, a genetic screen was performed to identify mutations that increase the mutation rates caused by weak mutator mutations such as exo1Delta and pms1-A130V mutations. In a screen starting with an exo1 mutation, exo1-dependent mutator mutations were obtained in MLH1, PMS1, MSH2, MSH3, POL30 (PCNA), POL32, and RNR1, whereas starting with the weak pms1 allele pms1-A130V, pms1-dependent mutator mutations were identified in MLH1, MSH2, MSH3, MSH6, and EXO1. These mutations only cause weak MMR defects as single mutants but cause strong MMR defects when combined with each other. Most of the mutations obtained caused amino acid substitutions in MLH1 or PMS1, and these clustered in either the ATP-binding region or the MLH1-PMS1 interaction regions of these proteins. The mutations showed two other types of interactions: specific pairs of mutations showed unlinked noncomplementation in diploid strains, and the defect caused by pairs of mutations could be suppressed by high-copy-number expression of a third gene, an effect that showed allele and overexpressed gene specificity. These results support a model in which EXO1 plays a structural role in MMR and stabilizes multiprotein complexes containing a number of MMR proteins. A similar role is proposed for PCNA based on the data presented.


Assuntos
Pareamento Incorreto de Bases , Reparo do DNA , Exodesoxirribonucleases/genética , Exodesoxirribonucleases/metabolismo , Mutação , Trifosfato de Adenosina/metabolismo , Alelos , Biblioteca Gênica , Teste de Complementação Genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , Fenótipo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ligação Proteica , Saccharomyces cerevisiae/metabolismo , Análise de Sequência de DNA , Supressão Genética
5.
Nature ; 411(6841): 1073-6, 2001 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-11429610

RESUMO

Gross chromosome rearrangements (GCRs), such as translocations, deletion of a chromosome arm, interstitial deletions and inversions, are often observed in cancer cells. Spontaneous GCRs are rare in Saccharomyces cerevisiae; however, the existence of mutator mutants with increased genome instability suggests that GCRs are actively suppressed. Here we show by genetic analysis that these genome rearrangements probably result from DNA replication errors and are suppressed by at least three interacting pathways or groups of proteins: S-phase checkpoint functions, recombination proteins and proteins that prevent de novo addition of telomeres at double-strand breaks (DSBs). Mutations that inactivate these pathways cause high rates of GCRs and show synergistic interactions, indicating that the pathways that suppress GCRs all compete for the same DNA substrates.


Assuntos
Rearranjo Gênico , Genoma Fúngico , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Dano ao DNA , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA/genética , Replicação do DNA , DNA Fúngico/biossíntese , DNA Fúngico/genética , Proteínas Fúngicas/metabolismo , Genes cdc , Mutação , Proteínas Recombinantes/metabolismo , Fase S/genética , Telomerase/antagonistas & inibidores , Telomerase/genética , Telomerase/metabolismo , Telômero , Translocação Genética
6.
J Biol Chem ; 276(34): 31487-93, 2001 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-11376001

RESUMO

The meiosis-specific MER3 protein of Saccharomyces cerevisiae is required for crossing over, which ensures faithful segregation of homologous chromosomes at the first meiotic division. The predicted sequence of the MER3 protein contains the seven motifs characteristic of the DExH-box type of DNA/RNA helicases. The purified MER3 protein is a DNA helicase, which can displace a 50-nucleotide fragment annealed to a single-stranded circular DNA. MER3 was found to have ATPase activity, which was stimulated either by single- or double-stranded DNA. The turnover rate, k(cat), of ATP hydrolysis was approximately 500/min in the presence of either DNA. MER3 was able to efficiently displace relatively long 631-nucleotide fragments from single-stranded circular DNA only in the presence of the S. cerevisiae single-stranded DNA-binding protein, RPA (replication protein A). It appears that RPA inhibits re-annealing of the single-stranded products of the MER3 helicase. The MER3 helicase was found to unwind DNA in the 3' to 5' direction relative to single-stranded regions in the DNA substrates. Possible roles for the MER3 helicase in meiotic crossing over are discussed.


Assuntos
Troca Genética/fisiologia , DNA Topoisomerases Tipo I/metabolismo , Proteínas de Ligação a DNA/fisiologia , Meiose/fisiologia , Adenosina Trifosfatases/metabolismo , Sequência de Bases , Primers do DNA , DNA Topoisomerases Tipo I/fisiologia , Ativação Enzimática
7.
Cell ; 104(3): 397-408, 2001 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-11239397

RESUMO

Cancer cells show increased genome rearrangements, although it is unclear what defects cause these rearrangements. Mutations in Saccharomyces cerevisiae RFC5, DPB11, MEC1, DDC2 MEC3, RAD53, CHK1, PDS1, and DUN1 increased the rate of genome rearrangements up to 200-fold whereas mutations in RAD9, RAD17, RAD24, BUB3, and MAD3 had little effect. The rearrangements were primarily deletion of a portion of a chromosome arm along with TEL1-dependent addition of a new telomere. tel1 mutations increased the proportion of translocations observed, and in some cases showed synergistic interactions when combined with mutations that increased the genome rearrangement rate. These data suggest that one role of S phase checkpoint functions in normal cells is to suppress spontaneous genome rearrangements resulting from DNA replication errors.


Assuntos
Cromossomos/genética , Endodesoxirribonucleases , Exodesoxirribonucleases , Fase S , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Supressão Genética , Telômero/fisiologia , Sequência de Bases , Deleção Cromossômica , Dano ao DNA , Replicação do DNA , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/fisiologia , Genótipo , Peptídeos e Proteínas de Sinalização Intracelular , Modelos Genéticos , Dados de Sequência Molecular , Mutagênese Insercional , Mutação , Proteínas Serina-Treonina Quinases , Saccharomyces cerevisiae/fisiologia , Homologia de Sequência do Ácido Nucleico , Transdução de Sinais , Translocação Genética
8.
Nat Genet ; 27(1): 113-6, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11138010

RESUMO

The Escherichia coli gene recQ was identified as a RecF recombination pathway gene. The gene SGS1, encoding the only RecQ-like DNA helicase in Saccharomyces cerevisiae, was identified by mutations that suppress the top3 slow-growth phenotype. Relatively little is known about the function of Sgs1p because single mutations in SGS1 do not generally cause strong phenotypes. Mutations in genes encoding RecQ-like DNA helicases such as the Bloom and Werner syndrome genes, BLM and WRN, have been suggested to cause increased genome instability. But the exact DNA metabolic defect that might underlie such genome instability has remained unclear. To better understand the cellular role of the RecQ-like DNA helicases, sgs1 mutations were analyzed for their effect on genome rearrangements. Mutations in SGS1 increased the rate of accumulating gross chromosomal rearrangements (GCRs), including translocations and deletions containing extended regions of imperfect homology at their breakpoints. sgs1 mutations also increased the rate of recombination between DNA sequences that had 91% sequence homology. Epistasis analysis showed that Sgs1p is redundant with DNA mismatch repair (MMR) for suppressing GCRs and for suppressing recombination between divergent DNA sequences. This suggests that defects in the suppression of rearrangements involving divergent, repeated sequences may underlie the genome instability seen in BLM and WRN patients and in cancer cases associated with defects in these genes.


Assuntos
Adenosina Trifosfatases/química , DNA Helicases/química , DNA Helicases/metabolismo , Genoma Fúngico , Recombinação Genética , Saccharomyces cerevisiae/genética , Adenosina Trifosfatases/genética , Sequência de Bases , Síndrome de Bloom/enzimologia , Síndrome de Bloom/genética , Quebra Cromossômica/genética , Fragilidade Cromossômica/genética , Cromossomos Fúngicos/genética , DNA Helicases/genética , Exodesoxirribonucleases , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genes Fúngicos/genética , Genes Fúngicos/fisiologia , Humanos , Cinética , Dados de Sequência Molecular , Mutação/genética , RecQ Helicases , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae , Homologia de Sequência , Síndrome de Werner/enzimologia , Síndrome de Werner/genética , Helicase da Síndrome de Werner
9.
Nat Genet ; 26(3): 375-8, 2000 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11062484

RESUMO

Proliferating cell nuclear antigen (PCNA) is required for mismatch repair (MMR) and has been shown to interact with complexes containing Msh2p or MLH1 (refs 1-4). PCNA has been implicated to act in MMR before and during the DNA synthesis step, although the biochemical basis for the role of PCNA early in MMR is unclear. Here we observe an interaction between PCNA and Msh2p-Msh6p mediated by a specific PCNA-binding site present in Msh6p. An msh6 mutation that eliminated the PCNA-binding site caused a mutator phenotype and a defect in the interaction with PCNA. The association of PCNA with Msh2p-Msh6p stimulated the preferential binding of Msh2p-Msh6p to DNA containing mispaired bases. Mutant PCNA proteins encoded by MMR-defective pol30 alleles were defective for interaction with Msh2p-Msh6p and for stimulation of mispair binding by Msh2p-Msh6p. Our results suggest that PCNA functions directly in mispair recognition and that mispair recognition requires a higher-order complex containing proteins in addition to Msh2p-Msh6p.


Assuntos
Pareamento Incorreto de Bases , Reparo do DNA , Proteínas de Ligação a DNA/fisiologia , Proteínas Fúngicas/fisiologia , Antígeno Nuclear de Célula em Proliferação/fisiologia , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Sequência de Aminoácidos , Sítios de Ligação , Sequência Consenso , DNA Fúngico/genética , DNA Fúngico/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas Fúngicas/genética , Substâncias Macromoleculares , Dados de Sequência Molecular , Proteína 2 Homóloga a MutS , Mutagênese Sítio-Dirigida , Antígeno Nuclear de Célula em Proliferação/genética , Ligação Proteica , Saccharomyces cerevisiae/fisiologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos
11.
Mol Cell ; 6(3): 593-603, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11030339

RESUMO

The Saccharomyces cerevisiae DNA polymerase delta proofreading exonuclease-defective mutation pol3-01 is known to cause high rates of accumulating mutations. The pol3-01 mutant was found to have abnormal cell cycle progression due to activation of the S phase checkpoint. Inactivation of the S phase checkpoint suppressed both the pol3-01 cell cycle progression defect and mutator phenotype, indicating that the pol3-01 mutator phenotype was dependent on the S phase damage checkpoint pathway. Epistasis analysis suggested that a portion of the pol3-01 mutator phenotype involves members of the RAD6 epistasis group that function in both error-free and error-prone repair. These results indicate that activation of a checkpoint in response to certain types of replicative defects can result in the accumulation of mutations.


Assuntos
Proteínas de Ciclo Celular , DNA Polimerase III/genética , Reparo do DNA/genética , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Sequência de Bases , DNA Polimerase III/metabolismo , Replicação do DNA/genética , Mutação da Fase de Leitura , Proteínas Fúngicas/genética , Deleção de Genes , Genótipo , Dados de Sequência Molecular , Mutagênese/fisiologia , Fenótipo , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases , Fase S/genética
12.
J Natl Cancer Inst ; 92(18): 1517-22, 2000 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-10995807

RESUMO

BACKGROUND: The incidence of hereditary nonpolyposis colon cancer (HNPCC) in the general population is not well defined because of the lack of large population-based studies. We characterized the incidence of HNPCC in a large, population-based cohort of colorectal cancer probands and analyzed the location of colorectal tumors. METHODS: Of the participating 1134 probands from three counties in Southern California, 907 had a negative family history of colorectal cancer and 227 had a positive family history of colorectal cancer. In addition, 11 referral case subjects with HNPCC were used to study mutation frequencies in two mismatch repair genes (MSH2 and MLH1) and microsatellite instability. All statistical tests were two-sided. RESULTS: Among the probands diagnosed in Orange County during 1994 (population-based sample, all ages), five were consistent with the Amsterdam criteria for HNPCC (0.9%; 95% confidence interval [CI] = 0. 3%-2.1%). Among probands diagnosed at less than 65 years of age-from the wider three-county area and a longer time span-16 (2.1%; 95% CI = 1.2%-3.4%) had a clinical history consistent with the Amsterdam criteria for HNPCC. Five (approximately 45%) of 11 of the referral HNPCC case subjects had a mutation in MSH2 or MLH1 and also showed microsatellite instability. The family members of case subjects with mutations tended to show an earlier age at diagnosis of HNPCC and more multiple primary cancers than those of case subjects without detectable mutations. Many of the known characteristics of HNPCC, including the presence of ureteral and endometrial cancers, were seen in both sets of families. The previously reported proximal location of colorectal tumors in HNPCC kindreds was not seen in the population-based dataset but was similar to the location reported in the referral cases. CONCLUSIONS: On the basis of our data, we believe that the prevalence of HNPCC in the general population is likely to be closer to 1% than to 5%. Furthermore, our study suggests that some previously reported characteristics of HNPCC, such as the proximal location of tumors in the syndrome, may not always hold true in a population-based sample.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação , Vigilância da População , Idoso , California/epidemiologia , Feminino , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade
13.
J Med Genet ; 37(9): 641-5, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10978352

RESUMO

BACKGROUND AND AIMS: There are multiple criteria for the clinical diagnosis of hereditary non-polyposis colorectal cancer (HNPCC). The value of several of the newer proposed diagnostic criteria in identifying subjects with mutations in HNPCC associated mismatch repair genes has not been evaluated, and the performance of the different criteria have not been formally compared with one another. METHODS: We classified 70 families with suspected hereditary colorectal cancer (excluding familial adenomatous polyposis) by several existing clinical criteria for HNPCC, including the Amsterdam criteria, the Modified Amsterdam criteria, the Amsterdam II criteria, and the Bethesda criteria. The results of analysis of the mismatch repair genes MSH2 and MLH1 by full gene sequencing were available for a proband with colorectal neoplasia in each family. The sensitivity and specificity of each of the clinical criteria for the presence of MSH2 and MLH1 mutations were calculated. RESULTS: Of the 70 families, 28 families fulfilled the Amsterdam criteria, 39 fulfilled the Modified Amsterdam Criteria, 34 fulfilled the Amsterdam II criteria, and 56 fulfilled at least one of the seven Bethesda Guidelines for the identification of HNPCC patients. The sensitivity and specificity of the Amsterdam criteria were 61% (95% CI 43-79) and 67% (95% CI 50-85). The sensitivity of the Modified Amsterdam and Amsterdam II criteria were 72% (95% CI 58-86) and 78% (95% CI 64-92), respectively. Overall, the most sensitive criteria for identifying families with pathogenic mutations were the Bethesda criteria, with a sensitivity of 94% (95% CI 88-100); the specificity of these criteria was 25% (95% CI 14-36). Use of the first three criteria of the Bethesda guidelines only was associated with a sensitivity of 94% and a specificity of 49% (95% CI 34-64). CONCLUSIONS: The Amsterdam criteria for HNPCC are neither sufficiently sensitive nor specific for use as a sole criterion for determining which families should undergo testing for MSH2 and MLH1 mutations. The Modified Amsterdam and the Amsterdam II criteria increase sensitivity, but still miss many families with mutations. The most sensitive clinical criteria for identifying subjects with pathogenic MSH2 and MLH1 mutations were the Bethesda Guidelines; a streamlined version of the Bethesda Guidelines may be more specific and easier to use in clinical practice.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Fatores Etários , Proteínas de Transporte , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Saúde da Família , Feminino , Humanos , Masculino , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Mutação , Proteínas Nucleares , Sensibilidade e Especificidade
14.
Genes Dev ; 14(9): 1085-97, 2000 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-10809667

RESUMO

Msh4 (MutS homolog 4) is a member of the mammalian mismatch repair gene family whose members are involved in postreplicative DNA mismatch repair as well as in the control of meiotic recombination. In this report we show that MSH4 has an essential role in the control of male and female meiosis. We demonstrate that MSH4 is present in the nuclei of spermatocytes early in prophase I and that it forms discrete foci along meiotic chromosomes during the zygotene and pachytene stages of meiosis. Disruption of the Msh4 gene in mice results in male and female sterility due to meiotic failure. Although meiosis is initiated in Msh4 mutant male and female mice, as indicated by the chromosomal localization of RAD51 and COR1 during leptonema/zygonema, the chromosomes fail to undergo normal pairing. Our results show that MSH4 localization on chromosomes during the early stages of meiosis is essential for normal chromosome synapsis in prophase I and that it acts in the same pathway as MSH5.


Assuntos
Mapeamento Cromossômico , Reparo do DNA , Regulação da Expressão Gênica no Desenvolvimento , Meiose/genética , Proteínas/genética , Proteínas/metabolismo , Animais , Pareamento Incorreto de Bases , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA/genética , Desenvolvimento Embrionário e Fetal , Feminino , Infertilidade Feminina/genética , Infertilidade Masculina/genética , Masculino , Camundongos , Camundongos Knockout , Rad51 Recombinase
15.
Trends Biochem Sci ; 25(4): 196-200, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10754554

RESUMO

Double-strand breaks in DNA can be repaired by homologous recombination including break-induced replication. In this reaction, the end of a broken DNA invades an intact chromosome and primes DNA replication resulting in the synthesis of an intact chromosome. Break-induced replication has also been suggested to cause different types of genome rearrangements.


Assuntos
Replicação do DNA , Genoma , Recombinação Genética , Dano ao DNA , Células Eucarióticas
16.
Cancer Res ; 60(4): 803-7, 2000 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-10706084

RESUMO

Repair of mismatches in DNA in mammalian cells is mediated by a complex of proteins that are members of two highly conserved families of genes referred to as MutS and MutL homologues. Germline mutations in several members of these families, MSH2, MSH6, MLH1, and PMS2, but not MSH3, are responsible for hereditary non-polyposis colorectal cancer. To examine the role of MSH3, we generated a mouse with a null mutation in this gene. Cells from Msh3-/- mice are defective in repair of insertion/ deletion mismatches but can repair base-base mismatches. Msh3-/- mice develop tumors at a late age. When the Msh3-/- and Msh6-/- mutations are combined, the tumor predisposition phenotype is indistinguishable from Msh2-/- or Mlh1-/- mice. These results suggest that MSH3 cooperates with MSH6 in tumor suppression.


Assuntos
Pareamento Incorreto de Bases/genética , Reparo do DNA/genética , Proteínas de Ligação a DNA/genética , Proteínas Fúngicas/genética , Neoplasias Intestinais/prevenção & controle , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas de Saccharomyces cerevisiae , Animais , Proteínas de Ligação a DNA/fisiologia , Feminino , Proteínas Fúngicas/fisiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 Homóloga a MutS , Mutação
17.
Am J Hum Genet ; 66(5): 1693-8, 2000 May.
Artigo em Inglês | MEDLINE | ID: mdl-10741953

RESUMO

Familial cold urticaria (FCU) is a rare autosomal dominant inflammatory disorder characterized by intermittent episodes of rash with fever, arthralgias, conjunctivitis, and leukocytosis. These symptoms develop after generalized exposure to cold. Some individuals with FCU also develop late-onset reactive renal amyloidosis, which is consistent with Muckle-Wells syndrome. By analyzing individuals with FCU from five families, we identified linkage to chromosome 1q44. Two-point linkage analysis revealed a maximum LOD score (Zmax) of 8.13 (recombination fraction 0) for marker D1S2836; multipoint linkage analysis identified a Zmax of 10. 92 in the same region; and haplotype analysis defined a 10.5-cM region between markers D1S423 and D1S2682. Muckle-Wells syndrome was recently linked to chromosome 1q44, which suggests that the two disorders may be linked to the same locus.


Assuntos
Cromossomos Humanos Par 1/genética , Temperatura Baixa , Urticária/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Amiloidose/complicações , Amiloidose/genética , Amiloidose/fisiopatologia , Criança , Pré-Escolar , Mapeamento Cromossômico , Doenças em Gêmeos/genética , Feminino , Genes Dominantes/genética , Marcadores Genéticos/genética , Haplótipos/genética , Humanos , Lactente , Nefropatias/complicações , Nefropatias/genética , Nefropatias/fisiopatologia , Escore Lod , Masculino , Pessoa de Meia-Idade , Linhagem , Penetrância , Software , Síndrome , Urticária/complicações , Urticária/fisiopatologia
19.
Biochim Biophys Acta ; 1470(1): R21-8, 2000 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-10656992

RESUMO

The Keystone Symposium on the Molecular Basis of Cancer was an excellent meeting, which stimulated the exchange of a great deal of information. This report was prepared to organize some of the results that provided new insights into the regulation of cell proliferation and apoptosis. We were unable to report on all of the talks and posters due mostly to our limited capacity to absorb and digest the large amount of results presented at the meeting. We apologize to those whose results were not covered in this report.


Assuntos
Proteínas de Transporte , Neoplasias/genética , Proteínas Adaptadoras de Transdução de Sinal , Animais , Apoptose , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Citoplasma/metabolismo , Reparo do DNA , Replicação do DNA , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição E2F , Genes Supressores de Tumor , Humanos , Camundongos , Proteína 1 Homóloga a MutL , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/fisiopatologia , Proteínas Nucleares/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteína de Replicação A , Proteína 1 de Ligação ao Retinoblastoma , Saccharomyces cerevisiae , Fator de Transcrição DP1 , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteína Tumoral p73 , Proteínas Supressoras de Tumor
20.
Nat Genet ; 24(1): 53-6, 2000 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-10615127

RESUMO

Inherited mutations in the mismatch repair (MMR) genes MSH2 and MLH1 are found in most hereditary nonpolyposis colon cancer (HNPCC) patients studied. Eukaryotic MMR uses two partially redundant mispair-recognition complexes, Msh2p-Msh6p and Msh2p-Msh3p (ref.2) Inactivation of MSH2 causes high rates of accumulation of both base-substitution and frameshift mutations. Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations; inactivation of MSH3 results in low rates of frameshift mutations. These different mutator phenotypes provide an explanation for the observation that MSH2 mutations are common in HNPCC families, whereas mutations in MSH3 and MSH6 are rare. We have identified novel missense mutations in Saccharomyces cerevisiae MSH6 that appear to inactivate both Msh2p-Msh6p- and Msh2p-Msh3p-dependent MMR. Our work suggests that such mutations may underlie some cases of inherited cancer susceptibility similar to those caused by MSH2 mutations.


Assuntos
Proteínas de Ligação a DNA , Proteínas Fúngicas/genética , Genes Dominantes , Mutação , Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Alelos , Pareamento Incorreto de Bases , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/genética , Humanos , Fenótipo
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