scholarly journals The role of DNA replication and isochores in generating mutation and silent substitution rate variance in mammals

1992 ◽  
Vol 60 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Adam Eyre Walker
Keyword(s):  
Dna Replication ◽  
Mutation Rate ◽  
Germ Line ◽  
Total Concentration ◽  
Silent Substitution ◽  
Nucleotide Pools ◽  
Free Nucleotide ◽  
Free Nucleotides ◽  
Line Selection

SummaryIt has been suggested that isochores are maintained by mutation biases, and that this leads to variation in the rate of mutation across the genome. A model of DNA replication is presented in which the probabilities of misincorporation and proofreading are affected by the composition and concentration of the free nucleotide pools. The relationship between sequence G + C content and the mutation rate is investigated. It is found that there is very little variation in the mutation rate between sequences of different G + C contents if the total concentration of the free nucleotides remains constant. However, variation in the mutation rate can be arbitrarily large if some mismatches are proofread and the total concentration of free nucleotides varies. Hence the model suggests that the maintenance of isochores by the replication of DNA in free nucleotide pools of biased composition does not lead per se to mutation rate variance. However, it is possible that changes in composition could be accompanied by changes in concentration, thus generating mutation rate variance. Furthermore, there is the possibility that germ-line selection could lead to alterations in the overall free nucleotide concentration through the cell cycle. These findings are discussed with reference to the variance in mammalian silent substitution rates.

scholarly journals Interactome Analysis of KIN (Kin17) Shows New Functions of This Protein

2021 ◽  
Vol 43 (2) ◽  
pp. 767-781
Author(s):  
Vanessa Pinatto Gaspar ◽  
Anelise Cardoso Ramos ◽  
Philippe Cloutier ◽  
José Renato Pattaro Junior ◽  
Francisco Ferreira Duarte Junior ◽  
...  
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Metabolism ◽  
Cell Types ◽  
Protein Protein Interactions ◽  
Cellular Mechanisms ◽  
Cancerous Cell ◽  
First Time

KIN (Kin17) protein is overexpressed in a number of cancerous cell lines, and is therefore considered a possible cancer biomarker. It is a well-conserved protein across eukaryotes and is ubiquitously expressed in all cell types studied, suggesting an important role in the maintenance of basic cellular function which is yet to be well determined. Early studies on KIN suggested that this nuclear protein plays a role in cellular mechanisms such as DNA replication and/or repair; however, its association with chromatin depends on its methylation state. In order to provide a better understanding of the cellular role of this protein, we investigated its interactome by proximity-dependent biotin identification coupled to mass spectrometry (BioID-MS), used for identification of protein–protein interactions. Our analyses detected interaction with a novel set of proteins and reinforced previous observations linking KIN to factors involved in RNA processing, notably pre-mRNA splicing and ribosome biogenesis. However, little evidence supports that this protein is directly coupled to DNA replication and/or repair processes, as previously suggested. Furthermore, a novel interaction was observed with PRMT7 (protein arginine methyltransferase 7) and we demonstrated that KIN is modified by this enzyme. This interactome analysis indicates that KIN is associated with several cell metabolism functions, and shows for the first time an association with ribosome biogenesis, suggesting that KIN is likely a moonlight protein.

scholarly journals Role of deoxycytidylate deaminase in deoxyribonucleotide synthesis in bacteriophage T4 DNA replication

1977 ◽  
Vol 252 (23) ◽  
pp. 8603-8608 ◽  
Author(s):  
C.S. Chiu ◽  
T. Ruettinger ◽  
J.B. Flanegan ◽  
G.R. Greenberg
Keyword(s):  
Dna Replication ◽  
Bacteriophage T4

scholarly journals Exceptional Chemotherapy Response in Metastatic Colorectal Cancer Associated With Hyper-Indel–Hypermutated Cancer Genome and Comutation of POLD1 and MLH1

2017 ◽  
pp. 1-12
Author(s):  
Manish R. Sharma ◽  
James T. Auman ◽  
Nirali M. Patel ◽  
Juneko E. Grilley-Olson ◽  
Xiaobei Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Somatic Mutation ◽  
Mutation Rate ◽  
Germ Line ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Response To Chemotherapy ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years. We sequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients with POLE- and/or POLD1-mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G>A [p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel–hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

scholarly journals Role of Papillomavirus E1 Initiator Dimerization in DNA Replication

2005 ◽  
Vol 79 (13) ◽  
pp. 8661-8664 ◽  
Author(s):  
Stephen Schuck ◽  
Arne Stenlund
Keyword(s):  
Dna Replication ◽  
Dna Binding ◽  
Dna Binding Domains ◽  
Binding Domains ◽  
Severe Effect ◽  
Origin Of Dna Replication ◽  
Initiation Of Dna Replication

ABSTRACT Viral initiator proteins are polypeptides that form oligomeric complexes on the origin of DNA replication (ori). These complexes carry out a multitude of functions related to initiation of DNA replication, and although many of these functions have been characterized biochemically, little is understood about how the complexes are assembled. Here we demonstrate that loss of one particular interaction, the dimerization between E1 DNA binding domains, has a severe effect on DNA replication in vivo but has surprisingly modest effects on most individual biochemical activities in vitro. We conclude that the dimer interaction is primarily required for initial recognition of ori.

Evidence for a pathogenic role of BRCA1 L1705P and W1837X germ-line mutations

2016 ◽  
Vol 43 (5) ◽  
pp. 335-338 ◽  
Author(s):  
Anna P. Sokolenko ◽  
Nikita M. Volkov ◽  
Elena V. Preobrazhenskaya ◽  
Evgeny N. Suspitsin ◽  
Aigul R. Garifullina ◽  
...  
Keyword(s):  
Germ Line ◽  
Pathogenic Role ◽  
Germ Line Mutations

Role of yeast Rth1 nuclease and its homologs in mutation avoidance, DNA repair, and DNA replication

1998 ◽  
Vol 34 (1) ◽  
pp. 21-29 ◽  
Author(s):  
Robert E. Johnson ◽  
Gopala K. Kovvali ◽  
Louise Prakash ◽  
S. Prakash
Keyword(s):  
Dna Repair ◽  
Dna Replication ◽  
Mutation Avoidance

AMPK blocks chromatin activation and consequent R-loop formation to protect genome stability following acute starvation

2021 ◽  
Author(s):  
Bing Sun ◽  
McLean Sherrin ◽  
Richard Roy
Keyword(s):  
Dna Damage ◽  
Genome Stability ◽  
Germ Line ◽  
Critical Role ◽  
Significant Proportion ◽  
Loop Formation ◽  
C Elegans ◽  
Chromatin Activation ◽  
Acute Starvation

Abstract During periods of starvation organisms must modify both gene expression and metabolic pathways to adjust to the energy stress. We previously reported that C. elegans that lack AMPK have transgenerational reproductive defects that result from abnormally elevated H3K4me3 levels in the germ line following recovery from acute starvation1. Here we show that H3K4me3 is dramatically increased at promoters, driving aberrant transcription elongation that results in the accumulation of R-loops in the starved AMPK mutants. DRIP-seq analysis demonstrated that a significant proportion of the genome was affected by R-loop formation with a dramatic expansion in the number of R-loops at numerous loci, most pronounced at the promoter-TSS regions of genes in the starved AMPK mutants. The R-loops are transmissible into subsequent generations, likely contributing to the transgenerational reproductive defects typical of these mutants following starvation. Strikingly, AMPK null germ lines show considerably more RAD-51 foci at sites of R-loop formation, potentially sequestering it from its critical role at meiotic breaks and/or at sites of induced DNA damage. Our study reveals a previously unforeseen role of AMPK in maintaining genome stability following starvation, where in its absence R-loops accumulate, resulting in reproductive compromise and DNA damage hypersensitivity.

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