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Physical Chemistry Chemical Physics :... Feb 2021Proton transfer along the hydrogen bonds of DNA can lead to the creation of short-lived, but biologically relevant point mutations that can further lead to gene mutation...
Proton transfer along the hydrogen bonds of DNA can lead to the creation of short-lived, but biologically relevant point mutations that can further lead to gene mutation and, potentially, cancer. In this work, the energy landscape of the canonical A-T and G-C base pairs (standard, amino-keto) to tautomeric A*-T* and G*-C* (non-standard, imino-enol) Watson-Crick DNA base pairs is modelled with density functional theory and machine-learning nudge-elastic band methods. We calculate the energy barriers and tunnelling rates of hydrogen transfer between and within each base monomer (A, T, G and C). We show that the role of tunnelling in A-T tautomerisation is statistically unlikely due to the presence of a small reverse reaction barrier. On the contrary, the thermal populations of the G*-C* point mutation could be non-trivial and propagate through the replisome. For the direct intramolecular transfer, the reaction is hindered by a substantial energy barrier. However, our calculations indicate that tautomeric bases in their monomeric form have remarkably long lifetimes.
Topics: Base Pairing; DNA; Density Functional Theory; Hydrogen Bonding; Isomerism; Models, Chemical; Point Mutation; Protons; Thermodynamics
PubMed: 33533770
DOI: 10.1039/d0cp05781a -
Journal of the American Association of... Aug 2022Mitochondrial disorders arise from DNA mutations in either the mitochondrial DNA (mtDNA) or nuclear DNA genomes. This article focuses on a mtDNA base-pair mutation...
Mitochondrial disorders arise from DNA mutations in either the mitochondrial DNA (mtDNA) or nuclear DNA genomes. This article focuses on a mtDNA base-pair mutation associated with neuropathy, ataxia, and retinitis pigmentosa and Leigh syndrome and the large-scale mtDNA deletion associated with Kearns-Sayre syndrome. Disease sequelae and management strategies are reviewed, along with implications for the nurse practitioner in primary or specialty care.
Topics: Humans; DNA, Mitochondrial; Point Mutation; Mitochondrial Diseases; Kearns-Sayre Syndrome; Mutation
PubMed: 36330549
DOI: 10.1097/JXX.0000000000000755 -
Microbial Drug Resistance (Larchmont,... Dec 2017Fluoroquinolone resistance in bacteria is usually associated with mutations in the topoisomerase regions. We report a novel point mutation in fluoroquinolone-resistant...
Fluoroquinolone resistance in bacteria is usually associated with mutations in the topoisomerase regions. We report a novel point mutation in fluoroquinolone-resistant Escherichia coli strains. E. coli isolated from the environment in and around Mangalore, India, were examined for their antimicrobial resistance profile to 12 antibiotics and for the antibiotic resistance genes by polymerase chain reaction. Of the 67 E. coli isolated, 24 (35.8%) were sensitive to all antibiotics and 43 (64.2%) showed resistance to at least one of the 12 antibiotics used in the study. One isolate (EC10) was resistant to nine of the 12 antibiotics used. Resistance to nalidixic acid was the most common (34.32%), followed by nitrofurantoin (26.86%), tetracycline (22.38%), ampicillin (20.89%), cotrimoxazole (13.43%), ciprofloxacin (11.94%), gentamicin (10.44%), piperacillin/tazobactam (7.46%), chloramphenicol (7.46%), and cefotaxime (4.47%). Least resistance was observed for meropenem (1.49%) and none of the isolates showed resistance to imipenem. All the isolates harbored resistance genes corresponding to their antimicrobial resistance. Few quinolone-resistant isolates carried single point mutation (ser83Leu) and some had double point mutation (Ser83Leu and Asp87Asn) in gyrA. A third novel point mutation was also observed at position 50 with the change in the amino acid from tyrosine to cysteine (Tyr50Cys) in gyrA region. The study throws light on a novel point mutation in fluoroquinolone-resistant isolates. While the study helps to understand the risk and occurrence of antibiotic resistance among gram-negative bacteria from the environment, the alarming rate of antibiotic-resistant bacteria is a cause of concern in addressing infections.
Topics: Anti-Bacterial Agents; DNA Gyrase; Drug Resistance, Multiple, Bacterial; Escherichia coli; Fluoroquinolones; India; Microbial Sensitivity Tests; Point Mutation; Quinolones
PubMed: 28445079
DOI: 10.1089/mdr.2016.0142 -
The CRISPR Journal Aug 2021
Topics: CRISPR-Cas Systems; Cytosine; Gene Editing; Guanidine; Humans; Mutagenesis; Point Mutation
PubMed: 34406044
DOI: 10.1089/crispr.2021.29134.kni -
BMC Medical Genomics Jan 2021In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to...
BACKGROUND
In addition to ovarian and breast cancers, loss-of-function mutations in BRCA1 and BRCA2 genes are also linked to an increased risk of pancreatic cancer, with ~ 4 to 7% of pancreatic cancer patients harboring germline BRCA mutations. Most BRCA alterations in pancreatic cancer are frame-shifting indels, stop-gain, and splice-site mutations, but single nucleotide substitutions are rare. Recent studies demonstrated a significant progression-free survival (PFS) benefit from maintenance olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor administered to patients with germline BRCA mutations and metastatic pancreatic cancer.
CASE PRESENTATION
Here, we report a metastatic pancreatic cancer case who harbored a novel somatic BRCA2 c.6944T > C (p. I2315T) point mutation. After 6 weeks first-line chemotherapy, the patient was refractory to treatment and had a progressive disease. Due to the novel nonsynonymous BRCA2 point mutation, we decided to change the strategy by administering olaparib. The patient benefited from olaparib therapy and achieved a PFS of ~ 6.5 months.
CONCLUSIONS
We describe a patient carrying a novel somatic BRCA2 p. I2315T point mutation, which is first reported in metastatic pancreatic cancer. This case report indicates that a gene mutation-based strategy should be considered in the clinic to provide more effective treatment.
Topics: Female; Genes, BRCA2; Humans; Pancreatic Neoplasms; Phthalazines; Piperazines; Point Mutation
PubMed: 33407459
DOI: 10.1186/s12920-020-00850-6 -
Methods in Molecular Biology (Clifton,... 2023DNA base editors, one of the CRISPR-based genome editing tools, can induce targeted point mutations at desired sites. Their superiority is based on the fact that they...
DNA base editors, one of the CRISPR-based genome editing tools, can induce targeted point mutations at desired sites. Their superiority is based on the fact that they can perform efficient and precise gene editing without generating a DNA double-strand break (DSB) or requiring a donor DNA template. Since they were first developed, significant efforts have been made to improve DNA base editors in order to overcome problems such as off-target edits on DNA/RNA and bystander mutations in editing windows. Here, we provide an overview of DNA base editors with a summary about the history of development of DNA base editors and report on efforts to improve them.
Topics: CRISPR-Cas Systems; Gene Editing; Mutation; Point Mutation; DNA
PubMed: 36592303
DOI: 10.1007/978-1-0716-2879-9_1 -
BMC Bioinformatics Oct 2020Genomic profiling of solid human tumors by projects such as The Cancer Genome Atlas (TCGA) has provided important information regarding the somatic alterations that...
BACKGROUND
Genomic profiling of solid human tumors by projects such as The Cancer Genome Atlas (TCGA) has provided important information regarding the somatic alterations that drive cancer progression and patient survival. Although researchers have successfully leveraged TCGA data to build prognostic models, most efforts have focused on specific cancer types and a targeted set of gene-level predictors. Less is known about the prognostic ability of pathway-level variables in a pan-cancer setting. To address these limitations, we systematically evaluated and compared the prognostic ability of somatic point mutation (SPM) and copy number variation (CNV) data, gene-level and pathway-level models for a diverse set of TCGA cancer types and predictive modeling approaches.
RESULTS
We evaluated gene-level and pathway-level penalized Cox proportional hazards models using SPM and CNV data for 29 different TCGA cohorts. We measured predictive accuracy as the concordance index for predicting survival outcomes. Our comprehensive analysis suggests that the use of pathway-level predictors did not offer superior predictive power relative to gene-level models for all cancer types but had the advantages of robustness and parsimony. We identified a set of cohorts for which somatic alterations could not predict prognosis, and a unique cohort LGG, for which SPM data was more predictive than CNV data and the predictive accuracy is good for all model types. We found that the pathway-level predictors provide superior interpretative value and that there is often a serious collinearity issue for the gene-level models while pathway-level models avoided this issue.
CONCLUSION
Our comprehensive analysis suggests that when using somatic alterations data for cancer prognosis prediction, pathway-level models are more interpretable, stable and parsimonious compared to gene-level models. Pathway-level models also avoid the issue of collinearity, which can be serious for gene-level somatic alterations. The prognostic power of somatic alterations is highly variable across different cancer types and we have identified a set of cohorts for which somatic alterations could not predict prognosis. In general, CNV data predicts prognosis better than SPM data with the exception of the LGG cohort.
Topics: DNA Copy Number Variations; Humans; Point Mutation; Prognosis
PubMed: 33081688
DOI: 10.1186/s12859-020-03791-0 -
The Analyst Apr 2022Single base mutations are closely related to cancer diagnosis and treatment. The fluorescent probe method is one of the important methods to detect single-base...
Single base mutations are closely related to cancer diagnosis and treatment. The fluorescent probe method is one of the important methods to detect single-base mutations. We constructed a universal probe detection system based on endonuclease IV and the DNA strand displacement reaction. The system uses two toehold strand displacement reactions to relay the mutation information to the universal strand. There is no need to design the probe one-by-one for each mutation point during multi-site detection. It has the advantages of simple operation, rapid detection, and low cost. We used this method to detect common clinical mutation sites (PTEN R130Q/EGFR L858R/PTEN rs1473918395), and the detection limit can reach 0.1%-1%. The detection system can provide a new rapid and economical method for clinical single-base mutation detection, and has broad application prospects in diagnosis and prognostic evaluation.
Topics: Biosensing Techniques; DNA; Deoxyribonuclease IV (Phage T4-Induced); Fluorescent Dyes; Mutation; Point Mutation
PubMed: 35311862
DOI: 10.1039/d1an02003j -
Advances in Experimental Medicine and... 2017The translocation t(8;21), leading to a fusion between the RUNX1 gene and the RUNX1T1 locus, was the first chromosomal translocation identified in cancer. Since the... (Review)
Review
The translocation t(8;21), leading to a fusion between the RUNX1 gene and the RUNX1T1 locus, was the first chromosomal translocation identified in cancer. Since the first description of this balanced rearrangement in a patient with acute myeloid leukemia (AML) in 1973, RUNX1 translocations and point mutations have been found in various myeloid and lymphoid neoplasms. In this chapter, we summarize the currently available data on the clinical relevance of core binding factor gene alterations in hematological disorders. In the first section, we discuss the prognostic implications of the core binding factor translocations RUNX1-RUNX1T1 and CBFB-MYH11 in AML patients. We provide an overview of the cooperating genetic events in patients with CBF-rearranged AML and their clinical implications, and review current treatment approaches for CBF AML and the utility of minimal residual disease monitoring. In the next sections, we summarize the available data on rare RUNX1 rearrangements in various hematologic neoplasms and the role of RUNX1 translocations in therapy-related myeloid neoplasia. The final three sections of the chapter cover the spectrum and clinical significance of RUNX1 point mutations in AML and myelodysplastic syndromes, in familial platelet disorder with associated myeloid malignancy, and in acute lymphoblastic leukemia.
Topics: Core Binding Factor Alpha 2 Subunit; Core Binding Factor beta Subunit; Hematologic Diseases; Humans; Leukemia, Myeloid, Acute; Point Mutation; Prognosis; Translocation, Genetic
PubMed: 28299658
DOI: 10.1007/978-981-10-3233-2_12 -
Pesticide Biochemistry and Physiology Jul 2019Pyrethroid-resistance in onion thrips, Thrips tabaci, has been reported in many countries including Japan. Identifying factors of the resistance is important to...
T929I and K1774N mutation pair and M918L single mutation identified in the voltage-gated sodium channel gene of pyrethroid-resistant Thrips tabaci (Thysanoptera: Thripidae) in Japan.
Pyrethroid-resistance in onion thrips, Thrips tabaci, has been reported in many countries including Japan. Identifying factors of the resistance is important to correctly monitoring the resistance in field populations. To identify pyrethroid-resistance related genes in T. tabaci in Japan, we performed RNA-Seq analysis of seven T. tabaci strains including two pyrethroid-resistant and five pyrethroid-susceptible strains. We identified a pair of single point mutations, T929I and K1774N, introducing two amino acid mutations, in the voltage-gated sodium channel gene, a pyrethroid target gene, in the two resistant strains. The K1774N is a newly identified mutation located in the fourth repeat domain of the sodium channel. Genotyping analysis of field-collected populations showed that most of the T. tabaci individuals in resistant populations carried the mutation pair, indicating that the mutation pair is closely associated with pyrethroid-resistance in Japan. Another resistance-related mutation, M918L, was also identified in part of the resistant populations. Most of the individuals with the mutation pair were arrhenotokous while all individuals with the M918L single mutation were thelytokous. The result of differentially expressed gene analysis revealed a small number of up-regulated detoxification genes in each resistant strain which might be involved in resistance to pyrethroid. However, no up-regulated detoxification genes common to the two resistant strains were detected. Our results indicate that the mutation pair in the sodium channel gene is the most important target for monitoring pyrethroid-resistance in T. tabaci, and that pyrethroid-resistant arrhenotokous individuals with the mutation pair are likely to be widely distributed in Japan.
Topics: Animals; Insecticide Resistance; Insecticides; Japan; Mutation; Point Mutation; Pyrethrins; Thysanoptera; Voltage-Gated Sodium Channels
PubMed: 31378364
DOI: 10.1016/j.pestbp.2019.04.012