Publications by authors named "Abu Amar M Al Mamun"

7 Publications

  • Page 1 of 1

Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.

N Engl J Med 2016 Jan 4;374(2):135-45. Epub 2015 Nov 4.

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist.

Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis.

Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH).

Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
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http://dx.doi.org/10.1056/NEJMoa1505917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775252PMC
January 2016

Identity and function of a large gene network underlying mutagenic repair of DNA breaks.

Science 2012 Dec;338(6112):1344-8

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030-3411, USA.

Mechanisms of DNA repair and mutagenesis are defined on the basis of relatively few proteins acting on DNA, yet the identities and functions of all proteins required are unknown. Here, we identify the network that underlies mutagenic repair of DNA breaks in stressed Escherichia coli and define functions for much of it. Using a comprehensive screen, we identified a network of ≥93 genes that function in mutation. Most operate upstream of activation of three required stress responses (RpoS, RpoE, and SOS, key network hubs), apparently sensing stress. The results reveal how a network integrates mutagenic repair into the biology of the cell, show specific pathways of environmental sensing, demonstrate the centrality of stress responses, and imply that these responses are attractive as potential drug targets for blocking the evolution of pathogens.
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http://dx.doi.org/10.1126/science.1226683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782309PMC
December 2012

Spontaneous mutagenesis is elevated in protease-defective cells.

Mol Microbiol 2009 Feb 24;71(3):629-39. Epub 2008 Nov 24.

University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Department of Microbiology and Molecular Genetics, International Center for Public Health, Newark, NJ 07101, USA.

As a first step towards describing the role of proteolysis in maintaining genomic integrity, we have determined the effect of the loss of ClpXP, a major energy-dependent cytoplasmic protease that degrades truncated proteins as well as a number of regulatory proteins, on spontaneous mutagenesis. In a rifampicin-sensitive to rifampicin-resistance assay that detects base substitution mutations in the essential rpoB gene, there is a modest, but appreciable increase in mutagenesis in Delta(clpP-clpX) cells relative to wild-type cells. A colony papillation analysis using a set of lacZ strains revealed that genetic -1 frameshift mutations are strongly elevated in Clp-defective cells. A quantitative analysis using a valine-sensitive to valine-resistance assay that detects frameshift mutations showed that mutagenesis is elevated 50-fold in Clp-defective cells. Elevated frameshift mutagenesis observed in Clp-deficient cells is essentially abolished in lexA1[Ind(-)] (SOS-uninducible) cells, and in cells deleted for the SOS gene dinB, which codes for DNA polymerase IV. In contrast, mutagenesis is unaffected or stimulated in cells deleted for umuC or umuD, which code for critical components of DNA polymerase V. Loss of rpoS, which codes for a stress-response sigma factor known to upregulate dinB expression in stationary phase, does not affect mutagenesis. We propose that elevated DinB expression, as well as stabilization of UmuD/UmuD' heterodimers in Delta(clpP-clpX) cells, contributes to elevated mutagenesis. These findings suggest that in normal cells, Clp-mediated proteolysis plays an important role in preventing gratuitous mutagenesis.
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http://dx.doi.org/10.1111/j.1365-2958.2008.06551.xDOI Listing
February 2009

Elevated expression of DNA polymerase II increases spontaneous mutagenesis in Escherichia coli.

Mutat Res 2007 Dec 18;625(1-2):29-39. Epub 2007 May 18.

University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Microbiology and Molecular Genetics, International Center for Public Health, 225 Warren Street, Newark, NJ 07101-1709, United States.

Escherichia coli DNA polymerase II (Pol-II), encoded by the SOS-regulated polB gene, belongs to the highly conserved group B (alpha-like) family of "high-fidelity" DNA polymerases. Elevated expression of polB gene was recently shown to result in a significant elevation of translesion DNA synthesis at 3, N(4)-ethenocytosine lesion with concomitant increase in mutagenesis. Here, I show that elevated expression of Pol-II leads to an approximately 100-fold increase in spontaneous mutagenesis in a manner that is independent of SOS, umuDC, dinB, recA, uvrA and mutS functions. Cells grow slowly and filament with elevated expression of Pol-II. Introduction of carboxy terminus ("beta interaction domain") mutations in polB eliminates elevated spontaneous mutagenesis, as well as defects in cell growth and morphology, suggesting that these abilities require the interaction of Pol-II with the beta processivity subunit of DNA polymerase III. Introduction of a mutation in the proofreading exo motif of polB elevates mutagenesis by a further 180-fold, suggesting that Pol-II can effectively compete with DNA polymerase III for DNA synthesis. Thus, Pol-II can contribute to spontaneous mutagenesis when its expression is elevated.
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http://dx.doi.org/10.1016/j.mrfmmm.2007.05.002DOI Listing
December 2007

Hypermutagenesis in mutA cells is mediated by mistranslational corruption of polymerase, and is accompanied by replication fork collapse.

Mol Microbiol 2006 Dec;62(6):1752-63

University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Microbiology and Molecular Genetics, International Center for Public Health, 225 Warren Street, Newark, NJ 07101-1709, USA.

Elevated mistranslation induces a mutator response termed translational stress-induced mutagenesis (TSM) that is mediated by an unidentified modification of DNA polymerase III. Here we address two questions: (i) does TSM result from direct polymerase corruption, or from an indirect pathway triggered by increased protein turnover? (ii) Why are homologous recombination functions required for the expression of TSM under certain conditions, but not others? We show that replication of bacteriophage T4 in cells expressing the mutA allele of the glyVtRNA gene (Asp-Gly mistranslation), leads to both increased mutagenesis, and to an altered mutational specificity, results that strongly support mistranslational corruption of DNA polymerase. We also show that expression of mutA, which confers a recA-dependent mutator phenotype, leads to increased lambdoid prophage induction (selectable in vivo expression technology assay), suggesting that replication fork collapse occurs more frequently in mutA cells relative to control cells. No such increase in prophage induction is seen in cells expressing alaVGlu tRNA (Glu-->Ala mistranslation), in which the mutator phenotype is recA-independent. We propose that replication fork collapse accompanies episodic hypermutagenic replication cycles in mutA cells, requiring homologous recombination functions for fork recovery, and therefore, for mutation recovery. These findings highlight hitherto under-appreciated links among translation, replication and recombination, and suggest that translational fidelity, which is affected by genetic and environmental signals, is a key modulator of replication fidelity.
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http://dx.doi.org/10.1111/j.1365-2958.2006.05490.xDOI Listing
December 2006

Escherichia coli DNA polymerase II can efficiently bypass 3,N(4)-ethenocytosine lesions in vitro and in vivo.

Mutat Res 2006 Jan 19;593(1-2):164-76. Epub 2005 Sep 19.

University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Microbiology and Molecular Genetics, International Center for Public Health, 225 Warren Street, Newark, NJ 07101-1709, USA.

Escherichia coli DNA polymerase II (pol-II) is a highly conserved protein that appears to have a role in replication restart, as well as in translesion synthesis across specific DNA adducts under some conditions. Here, we have investigated the effects of elevated expression of pol-II (without concomitant SOS induction) on translesion DNA synthesis and mutagenesis at 3,N(4)-ethenocytosine (varepsilonC), a highly mutagenic DNA lesion induced by oxidative stress as well as by exposure to industrial chemicals such as vinyl chloride. In normal cells, survival of transfected M13 single-stranded DNA bearing a single varepsilonC residue (varepsilonC-ssDNA) is about 20% of that of control DNA, with about 5% of the progeny phage bearing a mutation at the lesion site. Most mutations are C-->A and C-->T, with a slight predominance of transversions over transitions. In contrast, in cells expressing elevated levels of pol-II, survival of varepsilonC-ssDNA is close to 100%, with a concomitant mutation frequency of almost 99% suggesting highly efficient translesion DNA synthesis. Furthermore, an overwhelming majority of mutations at varepsilonC are C-->T transitions. Purified pol-II efficiently catalyzes translesion synthesis at varepsilonC in vitro, accompanied by high levels of mutagenesis with the same specificity. These results suggest that the observed in vivo effects in pol-II over-expressing cells are due to pol-II-mediated DNA synthesis. Introduction of mutations in the carboxy terminus region (beta interaction domain) of polB eliminates in vivo translesion synthesis at varepsilonC, suggesting that the ability of pol-II to compete with pol-III requires interaction with the beta processivity subunit of pol-III. Thus, pol-II can compete with pol-III for translesion synthesis.
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http://dx.doi.org/10.1016/j.mrfmmm.2005.07.016DOI Listing
January 2006

DNA polymerase III from Escherichia coli cells expressing mutA mistranslator tRNA is error-prone.

J Biol Chem 2002 Nov 24;277(48):46319-27. Epub 2002 Sep 24.

University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Department of Microbiology and Molecular Genetics, International Center for Public Health, Newark, New Jersey 07101-1709, USA.

Translational stress-induced mutagenesis (TSM) refers to the elevated mutagenesis observed in Escherichia coli cells in which mistranslation has been increased as a result of mutations in tRNA genes (such as mutA) or by exposure to streptomycin. TSM does not require lexA-regulated SOS functions but is suppressed in cells defective for homologous recombination genes. Crude cell-free extracts from TSM-induced E. coli strains express an error-prone DNA polymerase. To determine whether DNA polymerase III is involved in the TSM phenotype, we first asked if the phenotype is expressed in cells defective for all four of the non-replicative DNA polymerases, namely polymerase I, II, IV, and V. By using a colony papillation assay based on the reversion of a lacZ mutant, we show that the TSM phenotype is expressed in such cells. Second, we asked if pol III from TSM-induced cells is error-prone. By purifying DNA polymerase III* from TSM-induced and control cells, and by testing its fidelity on templates bearing 3,N(4)-ethenocytosine (a mutagenic DNA lesion), as well as on undamaged DNA templates, we show here that polymerase III* purified from mutA cells is error-prone as compared with that from control cells. These findings suggest that DNA polymerase III is modified in TSM-induced cells.
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http://dx.doi.org/10.1074/jbc.M206856200DOI Listing
November 2002