Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis最新文献

{"title":"The Kidney-Expressed Transcription Factor Zkscan3 is Dispensable for Autophagy Transcriptional Regulation and Aki Progression in Mouse","authors":"Huafeng Liu, Ze-jian Liu, Xiaoyu Li, Xingyu Li, Zixian Li, Huixia Chen, S-Q Gong, Minjie Zhang, Yaozhi Zhang, Zhihang Li, Lin Yang","doi":"10.2139/ssrn.4048743","DOIUrl":"https://doi.org/10.2139/ssrn.4048743","url":null,"abstract":"","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"1 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68684025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distribution of copy number variations and rearrangement endpoints in human cancers with a review of literature","authors":"Golrokh Mirzaei ,&nbsp;Ruben C. Petreaca","doi":"10.1016/j.mrfmmm.2021.111773","DOIUrl":"10.1016/j.mrfmmm.2021.111773","url":null,"abstract":"<div><p>Copy number variations<span> (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations<span> in Cancers (COSMIC) for our analysis. Indeed, we find that human cancers are characterized by specific patterns of chromosome rearrangements endpoints which in turn result in cancer specific CNVs. A review of the literature reveals tissue specific mutations which either drive these CNVs or appear as a consequence of CNVs because they confer an advantage to the cancer cell. We also identify several rearrangement endpoints hotspots that were not previously reported. Our analysis suggests that in addition to local chromosomal architecture, CNVs are driven by the internal cellular or nuclear physiology of each cancer tissue.</span></span></p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"824 ","pages":"Article 111773"},"PeriodicalIF":2.3,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9755472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide profiles of UV lesion susceptibility, repair, and mutagenic potential in melanoma","authors":"Brian S. Perez,&nbsp;Ka Man Wong,&nbsp;Erin K. Schwartz ,&nbsp;Rafael E. Herrera,&nbsp;Devin A. King,&nbsp;Pablo E. García-Nieto,&nbsp;Ashby J. Morrison","doi":"10.1016/j.mrfmmm.2021.111758","DOIUrl":"10.1016/j.mrfmmm.2021.111758","url":null,"abstract":"<div><p>Exposure to the ultraviolet (UV) radiation in sunlight creates DNA lesions, which if left unrepaired can induce mutations and contribute to skin cancer. The two most common UV-induced DNA lesions are the <em>cis-syn</em> cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs), both of which can initiate mutations. Interestingly, mutation frequency across the genomes of many cancers is heterogenous with significant increases in heterochromatin. Corresponding increases in UV lesion susceptibility and decreases in repair are observed in heterochromatin versus euchromatin. However, the individual contributions of CPDs and 6-4PPs to mutagenesis have not been systematically examined in specific genomic and epigenomic contexts. In this study, we compared genome-wide maps of 6-4PP and CPD lesion abundances in primary cells and conducted comprehensive analyses to determine the genetic and epigenetic features associated with susceptibility. Overall, we found a high degree of similarity between 6-4PP and CPD formation, with an enrichment of both in heterochromatin regions. However, when examining the relative levels of the two UV lesions, we found that bivalent and Polycomb-repressed chromatin states were uniquely more susceptible to 6-4PPs. Interestingly, when comparing UV susceptibility and repair with melanoma mutation frequency in these regions, disparate patterns were observed in that susceptibility was not always inversely associated with repair and mutation frequency. Functional enrichment analysis hint at mechanisms of negative selection for these regions that are essential for cell viability, immune function and induce cell death when mutated. Ultimately, these results reveal both the similarities and differences between UV-induced lesions that contribute to melanoma.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111758"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111758","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39263477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intronic variants of MITF (rs7623610) and CREB1 (rs10932201) genes may enhance splicing efficiency in human melanoma cell line","authors":"Juliana Carron ,&nbsp;Caroline Torricelli ,&nbsp;Janet Keller Silva ,&nbsp;Lilian de Oliveira Coser ,&nbsp;Carmen Silvia Passos Lima ,&nbsp;Gustavo Jacob Lourenço","doi":"10.1016/j.mrfmmm.2021.111763","DOIUrl":"10.1016/j.mrfmmm.2021.111763","url":null,"abstract":"<div><p><span>We previously reported that intronic single nucleotide variations (SNVs) in </span><span><em>MITF</em></span> (c.938−325G&gt;A, rs7623610) and <span><em>CREB1</em></span><span> (c.303+373G&gt;A, rs10932201) genes were associated with risk, aggressiveness, and prognosis of cutaneous melanoma<span> (CM). In this study, we investigated the influence of the above SNVs in splicing patterns and efficiency. We constructed minigenes with wild type and variant alleles from </span></span><em>MITF</em> and <em>CREB1</em><span><span> to assess the effect of the SNVs on splicing. The minigenes were transfected in the human melanoma cell line (SK-MEL-28). RT-PCR and </span>DNA sequencing investigated the constructs’ splicing patterns. Minigenes constructs’ splicing efficiency and </span><em>HNRNPA1</em> and <em>SF1</em> splicing genes’ expression were investigated by qPCR. We found that <em>MITF</em> and <em>CREB1</em> SNVs did not alter the splicing pattern, but they influenced the splicing efficiency. <em>MITF</em>-A (<em>p=</em> 0.03) and <em>CREB1</em>-A (<em>p</em>= 0.005) variant minigenes yielded an increase of mRNA generated from the constructions. Additionally, lower mRNA levels of <em>HNRNPA1</em> and <em>SF1</em> were seen in the variant minigenes <em>MITF</em>-A (<em>p</em>= 0.04) and <em>CREB1</em>-A (<em>p</em>= 0.005). We described for the first time the potential importance of <em>MITF</em> rs7623610 and <em>CREB1</em> rs10932201 SNVs in splicing efficiency and its relationship with CM.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111763"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39570741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutational property of newly identified mutagen l-glutamic acid γ-hydrazide in Escherichia coli","authors":"Tomoya Maeda ,&nbsp;Atsushi Shibai ,&nbsp;Naomi Yokoi ,&nbsp;Yumeko Tarusawa ,&nbsp;Masako Kawada ,&nbsp;Hazuki Kotani ,&nbsp;Chikara Furusawa","doi":"10.1016/j.mrfmmm.2021.111759","DOIUrl":"10.1016/j.mrfmmm.2021.111759","url":null,"abstract":"<div><p>We previously found that an <span>l</span>-glutamine analog <span>l</span>-glutamic acid γ-hydrazide has high mutagenic activity through the high-throughput laboratory evolution of <em>Escherichia coli</em>. In this study, mutagenicity and mutational property of <span>l</span>-glutamic acid γ-hydrazide were examined by the Ames test and mutation accumulation experiments using <em>E. coli</em>. The Ames test revealed that <span>l</span>-glutamic acid γ-hydrazide showed higher mutagenic activity without metabolic activation than known mutagens 2-aminoanthracene, and cobalt(II) acetate tetrahydrate. This result indicates that <span>l</span>-glutamic acid γ-hydrazide does not require metabolic activation for mutagenic activity in <em>E. coli</em>. Mutation accumulation experiments and whole-genome sequencing analysis revealed the number and spectrum of the accumulated mutations with or without <span>l</span>-glutamic acid γ-hydrazide. In the presence of <span>l</span>-glutamic acid γ-hydrazide, MDS42 strain accumulated 392.3 ± 116.2 point mutations during 30 passages corresponding to 777 generations, while MDS42 strain accumulated 1.5 ± 2.5 point mutations without <span>l</span>-glutamic acid γ-hydrazide during 50 passages corresponding to 1341 generations. The mutational spectrum of <span>l</span>-glutamic acid γ-hydrazide was G/C to A/T transition (82.2 ± 4.3 %) and A/T to G/C transition (17.4 ± 4.3 %). These results indicated that <span>l</span>-glutamic acid γ-hydrazide has a strong mutagenic activity.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111759"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111759","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39219264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The duration of exposure to 50 Hz magnetic fields: Influence on circadian genes and DNA damage responses in murine hematopoietic FDC-P1 cells","authors":"Ehab Mustafa ,&nbsp;Jukka Luukkonen ,&nbsp;Jenny Makkonen ,&nbsp;Jonne Naarala","doi":"10.1016/j.mrfmmm.2021.111756","DOIUrl":"10.1016/j.mrfmmm.2021.111756","url":null,"abstract":"<div><p>We investigated the effects of 50 Hz extremely low-frequency magnetic fields (MFs) on gene expression related to the circadian rhythm or DNA damage signaling and whether these fields modify DNA damage repair rate after bleomycin treatment. Murine FDC-P1 hematopoietic cells were exposed for different durations (15 min, 2 h, 12 h, and 24 h) to either 200 μT MFs or sham-exposures. Cells were then collected for comet assay or real-time PCR to determine immediate DNA damage level and circadian rhythm gene expression, respectively. To assess DNA-damage signaling and DNA repair rate, the cells were subsequently treated with 20 μg/mL bleomycin for 1 h and then either assayed immediately or allowed to repair their DNA for 1 or 2 h. We found that circadian rhythm-related genes were upregulated after 12 h of MF exposure and downregulated after 24 h of MF exposure, but none of the affected genes were core genes controlling the circadian rhythm. In addition, we found that the repair rate for bleomycin-induced damage was only decreased after MF exposure for 24 h. In conclusion, our findings suggest that the effects of MFs are duration-dependent; they were observed predominantly after long exposures.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111756"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111756","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39253043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dose-, LET-, and gene-dependent patterns of DNA changes underlying the point mutations in spermatozoa of Drosophila melanogaster. I. Autosomal gene black","authors":"I.D. Alexandrov,&nbsp;M.V. Alexandrova","doi":"10.1016/j.mrfmmm.2021.111755","DOIUrl":"10.1016/j.mrfmmm.2021.111755","url":null,"abstract":"<div><p>Sequence analysis of 7 spontaneous, 27 γ-ray- and 20 neutron/neutron+γ-ray-induced <em>black (b)</em> point mutants was carried out. All these mutants were isolated as non-mosaic transmissible recessive visibles in the progeny of irradiated males from the wild-type high-inbred laboratory D32 strain of <em>Drosophila melanogaster</em>. Among spontaneous mutants, there were two (28.5 %) mutants with <em>copia</em> insertion in intron 1 and exon 2, three (42.8 %) with replacement of <em>b^+D32</em> paternal sequence with maternal <em>b¹</em> sequence (gene conversion), one (14.3 %) with 142-bp-long insertion in exon 2, and one (14.3 %) with a short deletion and two single-base substitutions in exon 3. Among γ-ray-induced mutants, there were 1 (3.7 %) with <em>copia</em> insertion in intron 2, 6 (22.2 %) with gene conversion, and the remaining 20 (74.1 %) mutants had 37 different small-scale DNA changes. There were 20 (54.1 %) single- or double-base substitutions, 7 (18.9 %) frameshifts (indels), 9 (24.3 %) extended deletions or insertions, and 1(2.7 %) mutant with a short insertion instead of a short deletion. Remarkably, clusters of independent small-scale changes inside the gene or within one DNA helical turn were recovered. The spectrum of DNA changes in 20 neutron/ neutron+γ-ray-induced mutants was drastically different from that induced by γ-rays in that 18 (90.0 %) mutants had the <em>b¹</em>sequence. In addition, 2 (10.0 %) with gene conversion had 600- or 19-bp-long deletion in exon 3 and 1 (5.0 %) mutant with a short insertion instead of a short deletion. Analysis of all 27 mutants with gene conversion events shows that 20 (74.1 %) had full <em>b¹</em> sequence whereas 7 others (25.9 %) contained a partial <em>b</em>¹ sequence. These data are the first experimental evidence for gene conversion in the early stages of animal embryogenesis in the first diploid cleavage nucleus after male and female pronuclei have united. The gene conversion, frameshifts (indels), and deletions between short repeats were considered as products of a relevant DNA repair pathways described in the literature. As the first step, the gametic doubling doses for phenotypic <em>black</em> point mutations and for intragenic base substitution mutations in mature sperm cells irradiated by 40 Gy of γ-rays were estimated as 5.8 and 1.2 Gy, respectively, showing that doubling dose for mutations at the molecular level is about 5 times lower than that at the phenotypic level.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111755"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111755","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39078100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and characterization of inheritable structural variations induced by ion beam radiations in rice","authors":"Yunchao Zheng ,&nbsp;Shan Li ,&nbsp;Jianzhong Huang ,&nbsp;Haowei Fu ,&nbsp;Libin Zhou ,&nbsp;Yoshiya Furusawa ,&nbsp;Qingyao Shu","doi":"10.1016/j.mrfmmm.2021.111757","DOIUrl":"10.1016/j.mrfmmm.2021.111757","url":null,"abstract":"<div><p>High energy ion beams are effective physical mutagens for mutation induction in plants. Due to their high linear energy transfer (LET) property, they are known to generate single nucleotide variations (SNVs) and insertion/deletions (InDels, &lt;50 bp) as well as structural variations (SVs). However, due to the technical difficulties to identify SVs, studies on ion beam induced SVs by genome sequencing have so far been limited in numbers and inadequate in nature, and knowledge of SVs is scarce with regards to their characteristics. In the present study, we identified and validated SVs in six M₄ plants (designated as Ar_50, Ar_100, C_150, C_200, Ne_50 and Ne_100 according to ion beam types and irradiation doses), two each induced by argon (⁴⁰Ar¹⁸⁺), carbon (¹²C⁶⁺) and neon (²⁰Ne¹⁰⁺) ion beams and performed in depth analyses of their characteristics. In total, 22 SVs were identified and validated, consisting of 11 deletions, 1 duplication, and 4 intra-chromosomal and 6 inter-chromosomal translocations. There were several SVs larger than 1 kbp. The SVs were distributed across the whole genome with an aggregation with SNVs and InDels only in the Ne_50 mutants. An enrichment of a 11-bp wide G-rich DNA motif 'GAAGGWGGRGG' was identified around the SV breakpoints. Three mechanisms might be involved in the SV formation, i.e., the expansion of tandem repeats, transposable element insertion, and non-allelic homologous recombination. Put together, the present study provides a preliminary view of SVs induced by Ar, C and Ne ion beam radiations, and as a pilot study, it contributes to our understanding of how SVs might form after ion beam irradiation in rice.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111757"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111757","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39194493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced characterization of the thyA system for mutational analysis in Escherichia coli: Defining mutationally “hot” regions of the gene","authors":"Daniel Mashiach,&nbsp;Erin Mae Bacasen,&nbsp;Sunjum Singh,&nbsp;Timothy Kao,&nbsp;Lekha Yaramada,&nbsp;Daniel Mishail,&nbsp;Summer Singh,&nbsp;Jeffrey H. Miller","doi":"10.1016/j.mrfmmm.2021.111754","DOIUrl":"10.1016/j.mrfmmm.2021.111754","url":null,"abstract":"<div><p>We have extensively characterized base substitution mutations in the 795 base pair (bp) long <em>E. coli thyA</em> gene to define as many of the base substitution mutational sites that inactivate the gene as possible. The resulting catalog of mutational sites constitutes a system with up to 5 times as many sites for monitoring each of the six base substitution mutations as the widely used <em>rpoB</em>/Rif^r system. We have defined 75 sites for the G:C -&gt; A:T transition, 68 sites for the G:C -&gt; T:A transversion, 53 sites for the G:C -&gt; C:G transversion, 49 sites for the A:T -&gt; G:C transition, 39 sites for the A:T -&gt; T:A transversion, and 59 sites for the A:T -&gt; C:G transversion. The system is thus comprised of 343 base substitution mutations at 232 different base pairs, all of which can be sequenced with a single primer pair. This allows for the examination of mutational spectra using a more detailed probe of known mutations, while still allowing one to compare the number of repeated occurrences at specific sites. We have examined several mutagens and mutators with this system, and show its utility by looking at the spectrum of cisplatin, that has a single hotspot, underscoring the value of having as large an array of sites as possible at which one can monitor repeat occurrences. To test for regions of the gene that might be hotspots for a number of mutagens, or <strong>“</strong>hot” (mutaphilic) regions, we have looked at the ratio of mutations per set of an equal number of mutational sites throughout the gene. The resulting graphs suggest that there are “hot” regions at intervals, and this may reflect aspects of secondary structures, of the higher order structure of the chromosome, or perhaps the nucleoid structure of the chromosome plus histone-like protein complexes.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111754"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111754","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39081212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Origins of nonsense mutations in human tumor suppressor genes","authors":"Min Zhang,&nbsp;Da Yang,&nbsp;Barry Gold","doi":"10.1016/j.mrfmmm.2021.111761","DOIUrl":"10.1016/j.mrfmmm.2021.111761","url":null,"abstract":"<div><p>Understanding the origins of mutations in tumor suppressor genes and oncogenes associated with cancers in different tissues is critical to the development of potential prevention strategies. Analysis of &gt;10,000 nonsense mutations in 63 tumor suppressor genes based on the ratio of the number of nonsense mutations per codon type is reported for each gene. The ratio for C•G→T•A nonsense mutations at Arg CGA codons to the number of CGA codons in all cancers is 23 (3088 total nonsense mutations for 134 CGA codons in the 63 suppressor genes). The ratio for this codon, which is attributed to hydrolytic deamination of 5-methylcytosine at CpG sites based on the sequence context, is 6-fold higher than the next highest ratio that involves a C•G→T•A transition at Trp TGG codons. C•G→A•T transversions at Glu, Ser, Tyr, Gly and Cys codons account for 25 % of the total nonsense mutations but the mutation per codon ratio for these codons is 1.0. Analysis of the bases 5′ of the mutated CGA codons in the 63 tumor suppressor genes in all cancers shows a preference of 5′-G &gt; C ∼ T ∼ A, which is not indicative of a role for enzymatic deamination by deaminases. Overall C•G→T•A mutations account for 61 % of all of the nonsense mutations in the collection of tumor suppressor genes. It is demonstrated that the ratio of C•G→T•A deamination-associated nonsense mutations at CGA codons (hydrolytic deamination) to the number of frame shift insertion/deletion mutations (i.e., replication based) for 5 major tumor suppressors genes are very similar in 3 different tissues that undergo a wide range of stem cell divisions. Therefore, the frequency of deamination mutations parallels the number of stem cell replications. This may reflect the generation of more solvent accessible single-stranded DNA regions during polymerization that are kinetically more prone to deamination.</p></div>","PeriodicalId":49790,"journal":{"name":"Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis","volume":"823 ","pages":"Article 111761"},"PeriodicalIF":2.3,"publicationDate":"2021-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrfmmm.2021.111761","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39384299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}