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Houra Merrikh

Bio: Houra Merrikh is an academic researcher from Vanderbilt University. The author has contributed to research in topics: DNA replication & Gene. The author has an hindex of 22, co-authored 43 publications receiving 1623 citations. Previous affiliations of Houra Merrikh include Massachusetts Institute of Technology & University of Washington.


Papers
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Journal ArticleDOI
TL;DR: Findings are summarized which shed light on the significance of the problem and on how bacterial cells deal with unwanted encounters between the replication and transcription machineries.
Abstract: DNA replication and transcription use the same template and occur concurrently in bacteria. The lack of temporal and spatial separation of these two processes leads to their conflict, and failure to deal with this conflict can result in genome alterations and reduced fitness. In recent years major advances have been made in understanding how cells avoid conflicts between replication and transcription and how such conflicts are resolved when they do occur. In this Review, we summarize these findings, which shed light on the significance of the problem and on how bacterial cells deal with unwanted encounters between the replication and transcription machineries.

185 citations

Journal ArticleDOI
10 Aug 2017-Cell
TL;DR: It is shown that pervasive R-loop formation at head-on collision regions completely blocks replication, elevates mutagenesis, and inhibits gene expression, and that the resolution of these structures is critical for bacterial stress survival and pathogenesis.

176 citations

Journal ArticleDOI
24 Feb 2011-Nature
TL;DR: In vivo, co-directional transcription can disrupt replication, leading to the involvement of replication restart proteins, and in contrast to the findings in vitro, the replication restart machinery is involved in vivo in resolving potentially deleterious encounters due to head-on and co- Directional conflicts.
Abstract: Head-on encounters between the replication and transcription machineries on the lagging DNA strand can lead to replication fork arrest and genomic instability. To avoid head-on encounters, most genes, especially essential and highly transcribed genes, are encoded on the leading strand such that transcription and replication are co-directional. Virtually all bacteria have the highly expressed ribosomal RNA genes co-directional with replication. In bacteria, co-directional encounters seem inevitable because the rate of replication is about 10-20-fold greater than the rate of transcription. However, these encounters are generally thought to be benign. Biochemical analyses indicate that head-on encounters are more deleterious than co-directional encounters and that in both situations, replication resumes without the need for any auxiliary restart proteins, at least in vitro. Here we show that in vivo, co-directional transcription can disrupt replication, leading to the involvement of replication restart proteins. We found that highly transcribed rRNA genes are hotspots for co-directional conflicts between replication and transcription in rapidly growing Bacillus subtilis cells. We observed a transcription-dependent increase in association of the replicative helicase and replication restart proteins where head-on and co-directional conflicts occur. Our results indicate that there are co-directional conflicts between replication and transcription in vivo. Furthermore, in contrast to the findings in vitro, the replication restart machinery is involved in vivo in resolving potentially deleterious encounters due to head-on and co-directional conflicts. These conflicts probably occur in many organisms and at many chromosomal locations and help to explain the presence of important auxiliary proteins involved in replication restart and in helping to clear a path along the DNA for the replisome.

167 citations

Journal ArticleDOI
TL;DR: The authors show that when bacteria adapt to one plasmid, they become generally permissive to plasmids carriage, and suggest that poor plasmID persistence can be caused by a high cost involving helicase–plasmid interactions that can be rapidly ameliorated.
Abstract: Horizontal gene transfer mediated by broad-host-range plasmids is an important mechanism of antibiotic resistance spread. While not all bacteria maintain plasmids equally well, plasmid persistence can improve over time, yet no general evolutionary mechanisms have emerged. Our goal was to identify these mechanisms and to assess if adaptation to one plasmid affects the permissiveness to others. We experimentally evolved Pseudomonas sp. H2 containing multidrug resistance plasmid RP4, determined plasmid persistence and cost using a joint experimental–modelling approach, resequenced evolved clones, and reconstructed key mutations. Plasmid persistence improved in fewer than 600 generations because the fitness cost turned into a benefit. Improved retention of naive plasmids indicated that the host evolved towards increased plasmid permissiveness. Key chromosomal mutations affected two accessory helicases and the RNA polymerase β-subunit. Our and other findings suggest that poor plasmid persistence can be caused by a high cost involving helicase–plasmid interactions that can be rapidly ameliorated. Plasmids facilitate the evolution of antibiotic resistance but little is known about bacteria–plasmid evolution. Here, the authors show that when bacteria adapt to one plasmid, they become generally permissive to plasmid carriage.

144 citations

Journal ArticleDOI
TL;DR: It is suggested that AMR development can be inhibited through inactivation of evolvability factors (potentially with “anti-evolution” drugs)—in particular, Mfd—providing an unexplored route toward battling the AMR crisis.

138 citations


Cited by
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01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

2,187 citations

Journal ArticleDOI
TL;DR: The complex transition from exponential growth to stationary phase has been partially dissected by analyzing the induction of RpoS after specific stress treatments, and a better understanding has been led to a better, but still far from complete, understanding of how stresses lead to RPOS induction and what RPoS-dependent genes help the cell deal with the stress.
Abstract: Under conditions of nutrient deprivation or stress, or as cells enter stationary phase, Escherichia coli and related bacteria increase the accumulation of RpoS, a specialized sigma factor. RpoS-dependent gene expression leads to general stress resistance of cells. During rapid growth, RpoS translation is inhibited and any RpoS protein that is synthesized is rapidly degraded. The complex transition from exponential growth to stationary phase has been partially dissected by analyzing the induction of RpoS after specific stress treatments. Different stress conditions lead to induction of specific sRNAs that stimulate RpoS translation or to induction of small-protein antiadaptors that stabilize the protein. Recent progress has led to a better, but still far from complete, understanding of how stresses lead to RpoS induction and what RpoS-dependent genes help the cell deal with the stress.

802 citations

Journal ArticleDOI
TL;DR: This work concludes that the drift-barrier hypothesis is consistent with comparative measures of mutation rates, provides a simple explanation for the existence of error-prone polymerases and yields a formal counter-argument to the view that selection fine-tunes gene-specific mutation rates.
Abstract: Mutation is the source of genetic diversity on which natural selection acts, therefore understanding the rates of mutations is crucial for understanding evolutionary trajectories. In this Opinion article, the authors discuss how emerging experimental mutation-rate data from genome-wide sequencing studies, combined with population-genetic theory, can provide unifying explanations for the diversity in mutation rates between species and across genomic locations.

612 citations

Journal ArticleDOI
TL;DR: In this paper, the authors highlight the chief sources of double-strand break (DSB) and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination.
Abstract: DNA is subject to many endogenous and exogenous insults that impair DNA replication and proper chromosome segregation. DNA double-strand breaks (DSBs) are one of the most toxic of these lesions and must be repaired to preserve chromosomal integrity. Eukaryotes are equipped with several different, but related, repair mechanisms involving homologous recombination, including single-strand annealing, gene conversion, and break-induced replication. In this review, we highlight the chief sources of DSBs and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination.

577 citations

01 Jan 2014
TL;DR: This review highlights the chief sources of DSBs and crucial requirements for each of these repair processes, as well as the methods to identify and study intermediate steps in DSB repair by homologous recombination.
Abstract: Subject Collection DNA Recombination Models of Recombinational DNA RepairSources of DNA Double-Strand Breaks andAnuja Mehta and James E. HaberMeets DNATranscription and Recombination: When RNAAndres Aguilera and Helene GaillardMechanism and RegulationEnd Resection at Double-Strand Breaks:Lorraine S. SymingtonResection in Homologous RecombinationStructural Studies of DNA End Detection andChristian Linke-Winnebeck, et al.Christian Bernd Schiller, Florian Ulrich Seifert,The Dissolution of Double Holliday JunctionsAnna H. Bizard and Ian D. HicksonFor additional articles in this collection, see http://cshperspectives.cshlp.org/cgi/collection/ Copyright © 2014 Cold Spring Harbor Laboratory Press; all rights reservedDownloaded from http://cshperspectives.cshlp.org/

489 citations