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PubMed2025

Collateral mutagenesis funnels multiple sources of DNA damage into a ubiquitous mutational signature.

Mutations reflect the net effects of myriad types of damage, replication errors, and repair mechanisms, and thus are expected to differ across cell types with distinct exposures to mutagens, division rates, and cellular programs. Yet when mutations in humans are decomposed into a set of "signatures", one single base substitution signature, SBS5, is present across cell types and tissues, and predominates in post-mitotic neurons as well as male and female germlines [1-3]. The etiology of SBS5 is unknown. By modeling the processes by which mutations arise, we infer that SBS5 is the footprint of errors in DNA synthesis triggered by distinct types of DNA damage. Supporting this hypothesis, we find that SBS5 rates increase with signatures of endogenous and exogenous DNA damage in cancerous and non-cancerous cells and co-vary with repair rates along the genome as expected from model predictions. These analyses indicate that SBS5 captures the output of a "funnel", through which multiple sources of damage result in a similar mutation spectrum. As we further show, SBS5 mutations arise not only from translesion synthesis but also from DNA repair, suggesting that the signature reflects the occasional, shared use of a polymerase.

Journal Article↗

PubMed2025

TSC angiofibroma and ungual fibroma have different mutation signatures, with recurrent mutations in KMT2C.

PURPOSE: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome characterized by tumors affecting multiple tissues, including skin, due to inactivating TSC1/TSC2 variants. Genome-wide profiling of somatic mutations in a unique collection of angiofibroma (FAF) and ungual fibroma (UF) TSC skin tumors was performed. METHODS: Genome sequencing was performed on 9 samples, comprising 4 FAF and 5 UF, along with 6 matched normal samples from 6 individuals with TSC. RESULTS: TSC-FAF and TSC-UF skin tumors have different mutation signatures, with a predominance of UV-related single-nucleotide variant (SNV; SBS7a and SBS7b) and dinucleotide variant (DNV; DBS1) signatures in FAF, and aging-related SNV (SBS1 and SBS5) signatures in UF. We also identified a novel DNV signature for TSC-UF, with frequent TG>CA and TT>GG substitutions. Furthermore, 3 inactivating somatic mutations in KMT2C were observed in 2 of 4 TSC-FAF and 5 mutations in other cancer genes. CONCLUSION: The distinct SNV mutation signatures seen in TSC-FAF and UF indicate that they develop through distinct pathogenic mechanisms, UV-induced mutagenesis in FAF, and aging-related mutagenesis in UF. The mechanism of the novel DNV signature in UFs merits further investigation. Our observation on the occurrence of KMT2C mutations suggests that KMT2C inactivation contributes to the pathogenesis of TSC-FAF.

Humans↗

PubMed2026

Identification and validation of a previously missed mutational signature in colorectal cancer.

Mutational signature analysis has enhanced our understanding of mutagenic processes. In a recent study, we analyzed 802 microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was decomposed into SBS18. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from SBS18. Through an analysis of 2,616 CRCs across three independent cohorts, we demonstrate that SBS_D is consistently present, suggesting this signature may have been previously overlooked. We illustrate that the pattern of SBS_D better aligns with signatures associated with deficiencies in DNA repair, despite evidence that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in DNA repair-proficient CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development. SBS_D has been submitted to the COSMIC database and provisionally designated as SBS111.

Colorectal Neoplasms↗

PubMed2025

Identification and Validation of a Previously Missed Mutational Signature in Colorectal Cancer.

Mutational signature analysis has greatly enhanced our understanding of the mutagenic processes found in cancer and normal tissues. As part of a recent study, we analyzed 802 treatment-naïve, microsatellite-stable colorectal cancers (CRC) and identified a de novo signature, SBS_D, which was conservatively decomposed into SBS18, a signature associated with reactive oxygen species. Here, we re-evaluate this decomposition and provide evidence that SBS_D represents a distinct mutational process from that of SBS18. Through an independent analysis of 2,616 whole-genome sequenced microsatellite-stable CRCs across three distinct cohorts, we demonstrate that SBS_D is consistently present at a similar prevalence, suggesting that this signature may have been previously overlooked. Using a naïve decomposition approach, we demonstrate that the pattern of SBS_D better aligns with signatures previously associated with deficiencies in DNA polymerase delta (POLD1) proofreading and mismatch repair. However, multiple lines of evidence, including the absence of pathogenic mutations in the exonuclease domain of POLD1 or in mismatch repair-associated genes, indicate that SBS_D is not driven by canonical defects in these DNA repair pathways. Overall, this study identifies a previously unrecognized mutational signature in microsatellite-stable CRC and proposes that its etiology may be linked to DNA repair infidelity emerging late in tumor development in samples without canonical defects in DNA repair pathways.

Journal Article↗

PubMed2002

Mutational signature of the proximate bladder carcinogen N-hydroxy-4-acetylaminobiphenyl: inconsistency with the p53 mutational spectrum in bladder cancer.

We studied the mutagenicity of the proximate bladder carcinogen, N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) in embryonic fibroblasts of the Big Blue mouse. Treatment of these cells with increasing concentrations of N-OH-AABP for 24 h resulted in a dose-dependent increase in mutation frequency of the cII transgene up to 12.8-fold over the background. Single base substitutions comprised 86% of the N-OH-AABP-induced mutations and 74% of the spontaneous cII mutations (sequenced number of mutant plaques, 141 and 145, respectively). Of these, 63 and 36%, respectively, occurred at guanine residues along the cII gene. Whereas G to T transversions predominated in the induced cII mutations (47%), insertion was the most spontaneously derived cII mutation (19%). Mapping of N-OH-AABP-induced DNA adducts along the cII gene by terminal transferase-dependent PCR showed the formation of DNA adducts at specific nucleotide positions. Five preferential DNA adduction sites were established, of which four were major mutation sites for N-OH-AABP, especially for G to T transversions. This unique mutational signature of N-OH-AABP in the cII gene was, however, in sharp contrast with the mutational spectrum of the p53 gene in human bladder cancer. G to A transitions are the dominant type of p53 mutations (53%), being also prevalent in almost all of its five mutational hotspots (codons 175, 248, 273, 280, and 285). In addition, the majority of mutations in three of these hotspots (codons 175, 248, and 273) are at a methylated CpG site, whereas in the cII gene neither the preferential N-OH-AABP DNA adduction sites nor the induced mutational hotspots are biased toward methylated CpG dinucleotides. We conclude that N-OH-AABP leaves a characteristic mutational signature in the cII transgene, which is consistent with its preferential DNA adduction profile. However, the pattern of mutation induced by N-OH-AABP in the cII gene is largely at odds with the mutational spectrum of the p53 gene in human bladder cancer.

Aminobiphenyl Compounds↗

PubMed2025

Glioma mutational signatures associated with haloalkane exposure are enriched in firefighters.

BACKGROUND: Glioma is the most common malignant primary brain tumor and is associated with significant morbidity and mortality. Modifiable risk factors remain unidentified. New advances in exposure assessment, genomic analyses, and statistical techniques permit more accurate evaluation of glioma risk associated with exogenous occupational or environmental exposures. METHODS: By using whole-exome sequencing data from matched germline and glioma tumor samples, the authors compared tumor mutational signatures for 17 persons with glioma and a documented occupational history of firefighting with those of 18 persons with glioma without an occupational history of firefighting. All 35 individuals were participants in the University of California, San Francisco Adult Glioma Study. RESULTS: There was a positive correlation among firefighters between the median number of sample variants attributable to single-base substitution signature 42, a single-base substitution mutational signature associated with haloalkane exposure (from the Catalogue of Somatic Mutational Signatures in Cancer) and firefighting years (p = .04; R2 = 0.29). Among nonfirefighters, the individuals with the highest number of median variants attributable to single-base substitution signature 42 also had occupations that possibly exposed them to haloalkanes, such as painting and being a mechanic. CONCLUSIONS: In summary, the authors identified gliomas that had mutational signatures associated with haloalkane exposure that were enriched in firefighters and other occupations.

Humans↗

PubMed2004

Inverse PCR-based RFLP scanning identifies low-level mutation signatures in colon cells and tumors.

Detecting the presence and diversity of low-level mutations in human tumors undergoing genomic instability is desirable due to their potential prognostic value and their putative influence on the ability of tumors to resist drug treatment and/or metastasize. However, direct measurement of these genetic alterations in surgical samples has been elusive, because technical hurdles make mutation discovery impractical at low-mutation frequency levels (<10(-2)). Here, we describe inverse PCR-based amplified restriction fragment length polymorphism (iFLP), a new technology that combines inverse PCR, RFLP, and denaturing high-performance liquid chromatography to allow scanning of the genome at several thousand positions per experiment for low-level point mutations. Using iFLP, widespread, low-level mutations at mutation frequency 10(-2)-10(-4) were discovered in genes located on different chromosomes, e.g., OGG1, MSH2, PTEN, beta-catenin, Bcl-2, P21, ATK3, and Braf, in human colon cancer cells that harbor mismatch repair deficiency whereas mismatch repair-proficient cells were mutation free. Application of iFLP to the screening of sporadic colon cancer surgical specimens demonstrated widespread low-level mutations in seven out of 10 samples, but not in their normal tissue counterparts, and predicted the presence of millions of diverse, low-incidence mutations in tumors. Unique low-level mutational signatures were identified for each colon cancer cell line and tumor specimen. iFLP allows the high-throughput discovery and tracing of mutational signatures in human cells, precancerous lesions, and primary or metastatic tumors and the assessment of the number and heterogeneity of low-level mutations in surgical samples.

Base Pair Mismatch↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed1999

Ultraviolet radiation induced signature mutations in photocarcinogenesis.

The photons of sunlight begin a series of genetic events in skin leading to cancer. UV signature mutations provide an alternative to inherited mutations as a way of identifying genes that are involved in cancer development. They augment epidemiologic and clinical data by serving as molecular evidence for the role of UV radiation in skin carcinogenesis. Signature mutations are present in TP53 and PTCH, two tumor suppressor genes responsible for non-melanoma skin cancer. We review evidence that clones of TP53-mutated cells are present in normal human and murine epidermis exposed to UVB and conclude that, in addition to being a tumorigenic mutagen, sunlight acts as a tumor promoter by favoring the clonal expansion of TP53 mutated cells. These combined actions of sunlight result in normal individuals' carrying a substantial burden of keratinocytes predisposed to cancer. Thus cancer involves both a single-cell problem and a multi-cell problem; in skin cancer, sunlight appears to drive both.

Adult↗

PubMed2026

Mutational signatures in blood-brain barrier: mechanisms, computational insights, and clinical applications in precision oncology.

The blood - brain barrier (BBB) plays a central role in maintaining central nervous system (CNS) homeostasis, and its disruption is a defining feature of malignant brain tumors such as glioblastoma. Emerging evidence indicates that BBB dysfunction not only alters the tumor microenvironment but also shapes the mutational processes that drive genomic instability in CNS malignancies. This review synthesizes current understanding of the biological mechanisms linking BBB breakdown with distinct mutational signatures, including those arising from oxidative stress, hypoxia-induced replication stress, lipid peroxidation, inflammation, and metabolic reprogramming. Advances in next-generation sequencing, coupled with computational tools such as non-negative matrix factorization, Bayesian modeling, and deep learning, have enabled precise extraction of these signatures and their integration with multi-omics data. Clinically, BBB-associated mutational signatures offer significant promise for therapeutic stratification, prediction of treatment response, and noninvasive monitoring through cerebrospinal fluid - derived circulating tumor DNA. Despite these advances, challenges persist due to limited tissue accessibility, low-yield CSF samples, incomplete mechanistic models, and the lack of CNS-specific analytical frameworks. A deeper understanding of BBB-driven mutational processes, supported by improved computational approaches and integrative datasets, holds potential to advance precision oncology in neuro-oncology.

Humans↗

PubMed2002

Mutations of the p53 and PTCH gene in basal cell carcinomas: UV mutation signature and strand bias.

Mutations of p53 and PTCH gene, two candidate tumor suppressor genes for basal cell carcinoma (BCC), were screened in 15 cases of sporadic BCCs that developed in sun-exposed skin region in a Korean population. p53 and PTCH mutations were detected at a frequency of 33 and 40%, respectively, and the mutations were predominantly UV-signature transition, C-->T transitions at dipyrimidine sites and CC-->TT tandem mutations. In both genes, the most common mutations were missense mutations resulting in amino acid substitution, which is different than the results from Caucasian BCCs where mutations are frequently predicted to make truncated or absent proteins. All mutations, except for one, occurred on the nontranscribed strand where is little efficient removal of UV-induced pyrimidine dimers relative to the transcribed strand. Loss of heterozygocity (LOH) of 9q22 for PTCH loci was found in eight of 15 informative cases of BCCs (53%), but none of the cases were informative for LOH of 17p13 for p53 loci. Not only do our data indicate the key role played by p53 and PTCH in the development of BCCs, these findings also suggest that UVB may significantly contribute to BCC tumorigenesis. Moreover, molecular epidemiology composed of incidence of p53 and PTCH mutations, difference in the type of mutation and repair bias of UV-induced DNA lesions might affect the distinct features of BCCs between different racial population.

Aged↗

PubMed2006

Analysis of p53 mutations for a mutational signature in human intrahepatic cholangiocarcinoma.

Cholangiocarcinoma development may be related to cholangiocyte DNA damage from genotoxic compounds in bile. We have previously shown that human biliary tissue is exposed to genotoxic agents, as evidenced by the presence of DNA adducts. Establishing the presence of a 'mutational signature' in tumour suppressor genes from tumour tissue provides a means of linking cause and effect in human cancer. Inactivation of p53, known to have 'hot-spots' for particular chemical carcinogens, has previously been linked to human cholangiocarcinoma. However, previous p53 studies have focused on exons 5-8, potentially missing gene alterations at other sites. This study examined the putative link between environmental carcinogens and intrahepatic cholangiocarcinoma by analysing DNA from 31 patients for complete p53 mutational signatures, using single strand conformational polymorphism and polymerase chain reaction. All mutations found were compared to known p53 mutations in cholangiocarcinoma and to mutations induced by environmental mutagens, as described in p53 databases. Five non-silent p53 mutations were found, including three new frameshift mutations and two new intron mutations which have not previously been reported in cholangiocarcinoma. Two frameshifts were due to deletions and the third due to an insertion in exon 5. There was no predominant mutational spectrum amongst the set of cholangiocarcinoma samples studied, or on combining these mutations with the dataset of known p53 mutations in cholangiocarcinoma. Several reasons may explain this, including lack of data outside exons 5-8, bias in mutation reporting, the involvement of mutations in non-coding regions or genes other than p53, or the possibility that there is no carcinogenic specific agent and therefore no signature.

Base Sequence↗

PubMed2026

Polymerase-inhibitor drug synergy and mutational signatures in different epithelial cell models of RSVA and hPIV3 infection.

Despite the huge global health burden presented by respiratory viruses, effective broad-spectrum antiviral therapeutic options remain limited. Here we evaluated the antiviral activity of four RNA-dependent RNA polymerase (RdRp) inhibitors, remdesivir, ribavirin, favipiravir, and molnupiravir, as monotherapy or dual-drug combinations against respiratory syncytial virus (subtype A, RSVA) and human parainfluenza (serotype 3, hPIV3) using epithelial cell lines and primary human airway culture models. Remdesivir showed the greatest potency across both viruses, while ribavirin and favipiravir also demonstrated inhibition. Molnupiravir was active against RSVA but not hPIV3. Several dual-drug combinations, including remdesivir-favipiravir, remdesivir-molnupiravir and favipiravir-molnupiravir, produced marked synergy against RSVA, and more limited synergy for hPIV3. Antiviral efficacy was validated in primary airway epithelial cultures, where effective concentrations preserved epithelial integrity and attenuated viral disruption of ciliary function. Across both viruses, increasing antiviral exposure was associated with dose-dependent signature mutagenesis. Antivirals induced significantly higher RSVA mutation burden in the primary airway model. These findings highlight the therapeutic potential of RdRp inhibitor combinations for RSVA and hPIV3, provide mechanistic insight through antiviral-related mutational signatures, and demonstrate advantages of the primary human airway culture model for development of effective multi-drug regimens and broad-spectrum antiviral preparedness.

Journal Article↗

PubMed2000

Tumor-associated Apc mutations in Mlh1-/- Apc1638N mice reveal a mutational signature of Mlh1 deficiency.

Apc1638N mice, which are heterozygous for a germline mutation in Apc, typically develop three to five spontaneous intestinal tumors per animal. In most cases this is associated with allelic loss of wildtype Apc. We have previously reported that the multiplicity of intestinal tumors is increased dramatically by crossing Apc1638N with an Mlh1-deficient mouse strain that represents an animal model of hereditary non-polyposis colorectal cancer (HNPCC). The increased tumor multiplicity in these mice was associated with somatic mutations in the Apc tumor suppressor gene. Here, we have examined the nature and distribution of 91 Apc mutations implicated in the development of intestinal tumors in Mlh1-/- Apc1638N animals. Protein truncation mutations were detected in a majority of tumor samples, indicating that the prevailing mechanism of Apc mutation in tumors is altered from allelic loss to intragenic mutation as a result of Mlh1 deficiency. The observed mutations were a mixture of base substitutions (27%) and frameshifts (73%). Most frameshifts were detected within dinucleotide repeats and there were prominent mutational hotspots within sequences of this sort at codons 927-929, 1209-1211 and 1461-1464. The observed Apc mutations caused protein truncation upstream of the third 20 amino acid beta-catenin binding domain and the first Axin-binding SAMP repeat, yielding Apc proteins that are predicted to be deficient in destabilizing beta-catenin. Our results reveal a characteristic mutational signature in Apc that is attributable to Mlh1 deficiency. This demonstrates a direct effect of Mlh1 deficiency in the mutation of Apc in these tumors, and provides data that clarify the role of Mlh1 in mammalian DNA mismatch repair.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Microarray expression profiling in melanoma reveals a BRAF mutation signature.

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.

Amino Acid Substitution↗

PubMed2026

Mutational signature stratification of recurrent gliomas reveals distinct patterns of genomic traits.

BACKGROUND: Although temozolomide (TMZ) is widely used for glioma treatment, its therapeutic benefit is limited by acquired resistance and recurrence, facilitated by intratumor heterogeneity. Mutational signatures (MSs) inform tumor evolution and reveal alterations associated with treatment response. METHODS: We performed molecular analyses of 96 glioma recurrences with sufficient private single-nucleotide variants relative to their matched primary tumors, stratified by their dominant MS. RESULTS: Four groups were identified: MS11/TMZ-related (n = 38), MS1/5/aging-related (n = 32), MS6/15/21/26/microsatellite instability (MSI)-related (n = 13), and other MS-related recurrences (n = 13). MS11/TMZ-related recurrences showed higher acquired mutational counts than the other groups (1338 vs 59 (MS1/5/aging) vs 57 (MS6/15/21/26/MSI) vs 57 (other MSs); P < .01). Mutations in SYNE2, SZT2, and FBN3 were restricted to recurrences with dominant or second-dominant MS11/TMZ-related signature (n = 41), and 85% (35/41) harbored mutations in these genes. In MS11/TMZ-related recurrences with RNA sequencing data (n = 17), mRNA co-expression analyses identified SYNE2-ATAD5 and SZT2-MAPKBP1 associations. Among MS11/TMZ-related recurrences, MS23 was frequent (44%, 18/41) and associated with higher acquired mutational counts (2089 vs 1188; P = .018) and more IDH-wildtype tumors (67% vs 30%; P = .037). MAPKBP1 mutations were enriched in MS23-positive recurrences (56% (10/18) vs 0% (0/23); P < .001). MS1/5/aging-related recurrences showed more frequent acquired chromosome 16q losses (22% vs 8% (TMZ) vs 0% (MSI) vs 0% (other); P < .05), which were associated with an increased fraction of genome altered relative to 16q-diploid cases (15% vs 7%; P = .01). CONCLUSIONS: These findings show that MS-based stratification of recurrences refines molecular characterization after therapy and nominates candidate biomarkers and pathways for functional studies of treatment-associated glioma evolution.

mutational signatures↗

PubMed1999

A novel signature mutation for oxidative damage resembles a mutational pattern found commonly in human cancers.

To determine the types of mutations induced by oxidative damage, a kidney cell line with a heterozygous deficiency for the autosomal Aprt (adenine phosphoribosyltransferase) gene was tested for its mutagenic response to hydrogen peroxide. Aprt-deficient cells were selected and scored for loss of heterozygosity (LOH) for 11 microsatellite loci on mouse chromosome 8. On the basis of the LOH analysis, spontaneous mutants (n = 38) were distributed into four classes: apparent point mutation, mitotic recombination, chromosome loss, and large interstitial deletion. However, 9 of 20 (45%) hydrogen peroxide-induced mutants exhibited a novel class of mutations characterized by "discontinuous LOH" for one or more of the microsatellite loci. Interestingly, mutations resembling discontinuous LOH are commonly observed in a wide variety of human cancers. Our data suggest that discontinuous LOH is a signature mutational pattern for oxidative damage and further suggest that such genetic damage is widespread in cancer.

Adenine Phosphoribosyltransferase↗

PubMed2004

In vivo bypass efficiencies and mutational signatures of the guanine oxidation products 2-aminoimidazolone and 5-guanidino-4-nitroimidazole.

The in vivo mutagenic properties of 2-aminoimidazolone and 5-guanidino-4-nitroimidazole, two products of peroxynitrite oxidation of guanine, are reported. Two oligodeoxynucleotides of identical sequence, but containing either 2-aminoimidazolone or 5-guanidino-4-nitroimidazole at a specific site, were ligated into single-stranded M13mp7L2 bacteriophage genomes. Wild-type AB1157 Escherichia coli cells were transformed with the site-specific 2-aminoimidazolone- and 5-guanidino-4-nitroimidazole-containing genomes, and analysis of the resulting progeny phage allowed determination of the in vivo bypass efficiencies and mutational signatures of the DNA lesions. 2-Aminoimidazolone was efficiently bypassed and 91% mutagenic, producing almost exclusively G to C transversion mutations. In contrast, 5-guanidino-4-nitroimidazole was a strong block to replication and 50% mutagenic, generating G to A, G to T, and to a lesser extent, G to C mutations. The G to A mutation elicited by 5-guanidino-4-nitroimidazole implicates this lesion as a novel source of peroxynitrite-induced transition mutations in vivo. For comparison, the error-prone bypass DNA polymerases were overexpressed in the cells by irradiation with UV light (SOS induction) prior to transformation. SOS induction caused little change in the efficiency of DNA polymerase bypass of 2-aminoimidazolone; however, bypass of 5-guanidino-4-nitroimidazole increased nearly 10-fold. Importantly, the mutation frequencies of both lesions decreased during replication in SOS-induced cells. These data suggest that 2-aminoimidazolone and 5-guanidino-4-nitroimidazole in DNA are substrates for one or more of the SOS-induced Y-family DNA polymerases and demonstrate that 2-aminoimidazolone and 5-guanidino-4-nitroimidazole are potent sources of mutations in vivo.

Coliphages↗