Acetaldehyde forms covalent GG intrastrand crosslinks in DNA

Sonohara, Yuina; Yamamoto, Junpei; Tohashi, Kosuke; Takatsuka, Reine; Matsuda, Tomonari; Iwai, Shigenori; Kuraoka, Isao

doi:10.1038/s41598-018-37239-6

Cited by 36 publications

(28 citation statements)

References 29 publications

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“…We could not determine the damaged site in the oligonucleotide sequence ( Fig. 2a), suggesting the chemical instability of the lesions as previously reported [14].…”

Section: Nucleolytic Activity On Acetaldehyde-induced Dna Lesionssupporting

confidence: 43%

“…Previously, we reported that acetaldehyde reacts with adjacent deoxyguanosine residues on oligonucleotides, but not with single deoxyguanosine residues or any other deoxyadenosines, deoxycytosine or thymidine residues. It forms reversible intrastrand crosslinks with the GG dimer, which resembles the UV-induced dimer lesions, CPD and 6-4PP [14]. The current study indicated that acetaldehyde-treated plasmid DNA, which remained incomplete digested by restriction enzymes that recognize a GG sequence, was digested by restriction enzymes that recognize other sequences.…”

Section: Introductionmentioning

confidence: 60%

“…Previously, we reported that acetaldehyde forms reversible intrastrand GG crosslinks [14]. These crosslinks appear to be bulky DNA lesions, such as CPD and 6-4 pp.…”

Section: Discussionmentioning

confidence: 97%

“…Recently, we reported that acetaldehyde may induce GG intra crosslink lesions in reversible reactions [14]. To investigate the effects of the lesions on DNA metabolism, such as replication and transcription, we first analyzed the inhibitory effects exerted by the digestion of endonucleolytic and exonucleolytic enzymes.…”

Section: Nucleolytic Activity On Acetaldehyde-induced Dna Lesionsmentioning

confidence: 99%

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Effects of acetaldehyde-induced DNA lesions on DNA metabolism

et al. 2020

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Background: Acetaldehyde, produced upon exposure to alcohol, cigarette smoke, polluted air and sugar, is a highly reactive compound that is carcinogenic to humans and causes a variety of DNA lesions in living human cells. Previously, we reported that acetaldehyde reacts with adjacent deoxyguanosine residues on oligonucleotides, but not with single deoxyguanosine residues or other deoxyadenosine, deoxycytosine, or thymidine residues, and revealed that it forms reversible intrastrand crosslinks with the dGpdG sequence (GG dimer). Results: Here, we show that restriction enzymes that recognize a GG sequence digested acetaldehyde-treated plasmid DNA with low but significant efficiencies, whereas restriction enzymes that recognize other sequences were able to digest such DNA. This suggested that acetaldehyde produced GG dimers in plasmid DNA. Additionally, acetaldehyde-treated oligonucleotides were efficient in preventing digestion by the exonuclease function of T4 DNA polymerase compared to non-treated oligonucleotides, suggesting structural distortions of DNA caused by acetaldehyde-treatment. Neither in vitro DNA synthesis reactions of phi29 DNA polymerase nor in vitro RNA synthesis reactions of T7 RNA polymerase were observed when acetaldehyde-treated plasmid DNA was used, compared to when non-treated plasmid DNA was used, suggesting that acetaldehyde-induced DNA lesions inhibited replication and transcription in DNA metabolism. Conclusions: Acetaldehyde-induced DNA lesions could affect the relative resistance to endo-and exo-nucleolytic activity and also inhibit in vitro replication and in vitro transcription. Thus, investigating the effects of acetaldehydeinduced DNA lesions may enable a better understanding of the toxicity and carcinogenicity of acetaldehyde.

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“…We could not determine the damaged site in the oligonucleotide sequence ( Fig. 2a), suggesting the chemical instability of the lesions as previously reported [14].…”

Section: Nucleolytic Activity On Acetaldehyde-induced Dna Lesionssupporting

confidence: 43%

Section: Introductionmentioning

confidence: 60%

“…Previously, we reported that acetaldehyde forms reversible intrastrand GG crosslinks [14]. These crosslinks appear to be bulky DNA lesions, such as CPD and 6-4 pp.…”

Section: Discussionmentioning

confidence: 97%

Section: Nucleolytic Activity On Acetaldehyde-induced Dna Lesionsmentioning

confidence: 99%

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Effects of acetaldehyde-induced DNA lesions on DNA metabolism

et al. 2020

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“…The location of these tumors could reflect direct exposure to alcohol. Notably, no accumulation of somatic mutations (GG > TT) caused by acetaldehyde was observed in these tumors (data not shown). Signature 16 could be generated by direct exposure to alcohol, rather than its metabolites.…”

Section: Discussionmentioning

confidence: 87%

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy

et al. 2019

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Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole‐exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures—microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double‐strand break repair, and Signature 16—were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation‐driven tumorigenesis.

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Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

Ghodke

Pradeepkumar

2020

Eur J Org Chem

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The N2‐position of deoxyguanosine (dG) in DNA is susceptible to modification by various damaging agents. These modifications (lesions or adducts) can stall the DNA replication by replicative polymerases, and if the common DNA repair pathways do not remove them, it can result in genomic instability. This generally leads to the death or oncogenic transformation of the cell. An important mechanism to deal with this problem is Translesion synthesis (TLS), a bypass mechanism, which involves the tolerance of DNA damage by low‐fidelity DNA polymerases (TLS polymerases). To understand the accuracy of TLS polymerases, a chemical biology approach is required. In this review, we discuss the reliable methods to synthesize specific N2‐dG DNA adducts and how they are tolerated by bacterial TLS polymerase Pol IV and its mammalian orthologue hpol κ. Molecular insights on the accurate bypass of these adducts emerge from the primer extension assays, X‐ray crystallographic, and molecular modeling studies are reviewed here.

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Acetaldehyde forms covalent GG intrastrand crosslinks in DNA

Cited by 36 publications

References 29 publications

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy

Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

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Acetaldehyde forms covalent GG intrastrand crosslinks in DNA

Cited by 36 publications

References 29 publications

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

Effects of acetaldehyde-induced DNA lesions on DNA metabolism

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy

Site‐Specific N2‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass

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Site‐Specific N²‐dG DNA Adducts: Formation, Synthesis, and TLS Polymerase‐Mediated Bypass