Kenneth C. Carter

Bio: Kenneth C. Carter is an academic researcher from University of Massachusetts Amherst. The author has contributed to research in topics: Chromatin & Cell nucleus. The author has an hindex of 14, co-authored 19 publications receiving 5262 citations. Previous affiliations of Kenneth C. Carter include GlaxoSmithKline & Human Genome Sciences.

Mutation of a mutL homolog in hereditary colon cancer

Abstract: Some cases of hereditary nonpolyposis colorectal cancer (HNPCC) are due to alterations in a mutS-related mismatch repair gene. A search of a large database of expressed sequence tags derived from random complementary DNA clones revealed three additional human mismatch repair genes, all related to the bacterial mutL gene. One of these genes (hMLH1) resides on chromosome 3p21, within 1 centimorgan of markers previously linked to cancer susceptibility in HNPCC kindreds. Mutations of hMLH1 that would disrupt the gene product were identified in such kindreds, demonstrating that this gene is responsible for the disease. These results suggest that defects in any of several mismatch repair genes can cause HNPCC.

Mutations of two PMS homologues in hereditary nonpolyposis colon cancer.

Abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is one of man's commonest hereditary diseases. Several studies have implicated a defect in DNA mismatch repair in the pathogenesis of this disease. In particular, hMSH2 and hMLH1 homologues of the bacterial DNA mismatch repair genes mutS and mutL, respectively, were shown to be mutated in a subset of HNPCC cases. Here we report the nucleotide sequence, chromosome localization and mutational analysis of hPMS1 and hPMS2, two additional homologues of the prokaryotic mutL gene. Both hPMS1 and hPMS2 were found to be mutated in the germline of HNPCC patients. This doubles the number of genes implicated in HNPCC and may help explain the relatively high incidence of this disease.

Molecular cloning and functional expression of a human cDNA encoding the antimutator enzyme 8-hydroxyguanine-DNA glycosylase

Abstract: The major mutagenic base lesion in DNA caused by exposure to reactive oxygen species is 8-hydroxyguanine (8-oxo-7,8-dihydroguanine). In bacteria and Saccharomyces cerevisiae, this damaged base is excised by a DNA glycosylase with an associated lyase activity for chain cleavage. We have cloned, sequenced, and expressed a human cDNA with partial sequence homology to the relevant yeast gene. The encoded 47-kDa human enzyme releases free 8-hydroxyguanine from oxidized DNA and introduces a chain break in a double-stranded oligonucleotide specifically at an 8-hydroxyguanine residue base paired with cytosine. Expression of the human protein in a DNA repair-deficient E. coli mutM mutY strain partly suppresses its spontaneous mutator phenotype. The gene encoding the human enzyme maps to chromosome 3p25. These results show that human cells have an enzyme that can initiate base excision repair at mutagenic DNA lesions caused by active oxygen.

A three-dimensional view of precursor messenger RNA metabolism within the mammalian nucleus

Abstract: A quantitative three-dimensional analysis of nuclear components involved in precursor messenger RNA metabolism was performed with a combination of fluorescence hybridization, immunofluorescence, and digital imaging microscopy. Polyadenylate [poly(A)] RNA-rich transcript domains were discrete, internal nuclear regions that formed a ventrally positioned horizontal array in monolayer cells. A dimmer, sometimes strand-like, poly(A) RNA signal was dispersed throughout the nucleoplasm. Spliceosome assembly factor SC-35 localized within the center of individual domains. These data support a nuclear model in which there is a specific topological arrangement of noncontiguous centers involved in precursor messenger RNA metabolism, from which RNA transport toward the nuclear envelope radiates.

Discrete nuclear domains of poly(A) RNA and their relationship to the functional organization of the nucleus

Abstract: The functional organization of the nucleus was studied using a fluorescence microscopy approach which allowed integration of positional information for RNA, DNA, and proteins. In cells from sea urchin to human, nuclear poly(A) RNA was found concentrated primarily within several discrete "transcript domains" which often surrounded nucleoli. Concentrations of poly(A) RNA were coincident with snRNP antigen clusters, providing evidence for the localization of pre-mRNA splicing at these sites. The spatial relationship of transcript domains with respect to various classes of DNA was established, in that the poly(A) RNA-rich regions coincided with discrete regions of low DNA density and were non-randomly distributed with respect to specific DNA sequences. Centromeric DNA and late-replicating DNA did not overlap transcript domains, whereas a subset of early-replicating DNA may. Results indicate that transcript domains do not result directly from a simple clustering of chromatin corresponding to metaphase chromosomes bands. Finally, observations on the reassembly of these domains after mitosis suggest that the clustering of snRNP antigens may be dependent on the reappearance of pol II transcription. Implications of these findings for overall nuclear structure and function are considered, including a discussion of whether transcript domains may be sites of polymerase II transcription reflecting a clustering of active genes.

Genetic instabilities in human cancers

Abstract: Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

sources and effects of ionizing radiation

Abstract: NOTE The report of the Committee without its annexes appears as Official Records of the General Assembly, Sixty-third Session, Supplement No. 46. The designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the United Nations concerning the legal status of any country, territory, city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries. The country names used in this document are, in most cases, those that were in use at the time the data were collected or the text prepared. In other cases, however, the names have been updated, where this was possible and appropriate, to reflect political changes. Scientific Annexes Annex A. Medical radiation exposures Annex B. Exposures of the public and workers from various sources of radiation INTROdUCTION 1. In the course of the research and development for and the application of atomic energy and nuclear technologies, a number of radiation accidents have occurred. Some of these accidents have resulted in significant health effects and occasionally in fatal outcomes. The application of technologies that make use of radiation is increasingly widespread around the world. Millions of people have occupations related to the use of radiation, and hundreds of millions of individuals benefit from these uses. Facilities using intense radiation sources for energy production and for purposes such as radiotherapy, sterilization of products, preservation of foodstuffs and gamma radiography require special care in the design and operation of equipment to avoid radiation injury to workers or to the public. Experience has shown that such technology is generally used safely, but on occasion controls have been circumvented and serious radiation accidents have ensued. 2. Reviews of radiation exposures from accidents have been presented in previous UNSCEAR reports. The last report containing an exclusive chapter on exposures from accidents was the UNSCEAR 1993 Report [U6]. 3. This annex is aimed at providing a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and numbers of deaths and injuries, and the general trends for various practices. Its conclusions are to be seen in the context of the Committee's overall evaluations of the levels and effects of exposure to ionizing radiation. 4. The Committee's evaluations of public, occupational and medical diagnostic exposures are mostly concerned with chronic exposures of …

Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis

Abstract: The p53 tumor suppressor gene has come to the forefront of cancer research because it is commonly mutated in human cancer and the spectrum of p53 mutations in these cancers is providing clues to the etiology and molecular pathogenesis of neoplasia (1—3). Detection of p53 abnormalities may have diagnostic, prognostic, and therapeutic implications (4). The 15-year history of p53 investigations is a paradigm in cancer research, illustrating the convergence of previously parallel lines of basic, clinical, and epidemiological investigation and the rapid trans fer of research findings from the laboratory to the clinic. p53 is clearly a component in biochemical pathways central to human carcinogen esis; p53 protein alterations due to missense mutations and loss of p53 protein by nonsense or frameshift mutations provide a selective ad vantage for clonal expansion of preneoplastic and neoplastic cells (5). The potential for a missense mutation to cause loss of tumor suppres sor function and gain of oncogenic activity, i.e., to transform cells by two mechanisms, is one explanation for the commonality of p53 mutations in human cancer. Recent studies investigating the mecha nisms underlying the biological activity of p53 indicate that the protein is involved in gene transcription, DNA synthesis and repair, genomic plasticity, and programmed cell death (1—6).These complex biochemical processes are performed by multicomponent protein ma chines; therefore, it is not surprising that the p53 protein forms complexes with other cellular proteins (Fig. 1) and that some viral oncoproteins alter the functions of these machines by binding to p53 and perturbing its interaction with other cellular protein components. In this Perspective, we will focus on the origin of p.53 mutations, the mutational spectrum of p.53 in human cancers, and the hypotheses generated by the analysis of p53 mutations in premalignant and malignant cells. The interpretation ofp53 mutations in human cancers is based on observations of the patterns of DNA damage induced by chemical and physical mutagens in model systems. In this Introduc tion, we will review these data, which provide the background for many of the inferences drawn from p53 mutational analysis.