DNA-protein crosslink formation by endogenous aldehydes and AP sites

Nakamura, Jun; Nakamura, Mai

doi:10.1016/j.dnarep.2020.102806

Cited by 48 publications

(38 citation statements)

References 90 publications

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“…Therefore, endogenous formaldehyde may be elevated in people with ALDH2*1/*2 and ALDH2*2/*2. Recent studies have reported that aldehydes such as formaldehyde and acetaldehyde are complexed to form 1,4-dihydropyrdine-lysine adducts [3,6,28], which is an inflammatory, oxidation-specific epitope that can cause the inhibition of osteogenesis [29,30]. The increased formation of 1,4-dihydropyrdine-lysine adducts in the bone of individuals with the ALDH2*2 allele could cause worse osteoporosis than individuals with ALDH2*1/*1.…”

Section: Resultsmentioning

confidence: 99%

“…The carbonyl group of formaldehyde reacts with amino moieties of DNA and proteins, causing genotoxicity and impaired protein function. For the last two decades, our research interest has been focused on endogenous formaldehyde, and we have proposed that endogenous formaldehyde is a causative agent of noninfectious inflammation, including atherosclerosis [3], and plays an important role in the human hereditary disease Fanconi anemia [5,6]. Regarding the genotoxicity of formaldehyde, we first demonstrated that chicken DT40 B-lymphocytic cells deficient in the FANC/BRCA pathways are sensitive to physiological levels of formaldehyde (LC50:~5 μM) and the 2-carbon carbonyl compound acetaldehyde at fairly high concentrations (LC50: 2500 μM) [5,7].…”

Section: Introductionmentioning

confidence: 99%

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The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

et al. 2020

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Background: Exogenous formaldehyde is classified by the IARC as a Category 1 known human carcinogen. Meanwhile, a significant amount of endogenous formaldehyde is produced in the human body; as such, formaldehyde-derived DNA and protein adducts have been detected in animals and humans in the absence of major exogenous formaldehyde exposure. However, the toxicological effects of endogenous formaldehyde on individuals with normal DNA damage repair functions are not well understood. In this study, we attempted to generate C57BL/6 mice deficient in both Adh5 and Aldh2, which encode two major enzymes that metabolize endogenous formaldehyde, in order to understand the effects of endogenous formaldehyde on mice with normal DNA repair function. Results: Due to deficiencies in both ADH5 and ALDH2, few mice survived past post-natal day 21. In fact, the survival of pups within the first few days after birth was significantly decreased. Remarkably, two Aldh2 −/− /Adh5 −/− mice survived for 25 days after birth, and we measured their total body weight and organ weights. The body weight of Aldh2 −/− /Adh5 −/− mice decreased significantly by almost 37% compared to the Aldh2 −/− /Adh5 +/− and Aldh2 −/− /Adh5 +/+ mice of the same litter. In addition, the absolute weight of each organ was also significantly reduced. Conclusion: Mice deficient in both formaldehyde-metabolizing enzymes ADH5 and ALDH2 were found to develop partial synthetic lethality and mortality shortly after birth. This phenotype may be due to the accumulation of endogenous formaldehyde. No serious phenotype has been reported in people with dysfunctional, dominantnegative ALDH2*2 alleles, but it has been reported that they may be highly susceptible to osteoporosis and neurodegenerative diseases. It is important to further investigate these diseases in individuals with ALDH2*2 alleles, including an association with decreased metabolism, and thus accumulation, of formaldehyde.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

et al. 2020

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“…The ubiquitinated ID2 complex protects the replication forks and regulates the activity of the proteins involved in the processing of the ICL, enabling the recruitment of the proteins of the fourth module. 4) Homologous recombination (HR) by downstream proteins. Proteins acting downstream in the FA/BRCA pathway include BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN, RAD51C/FANCO, RAD51/FANCR, BRCA1/FANCS, XRCC2/FANCU, XPF/FANCQ, SLX4/FANCP, REV7/FANCV and RFWD3/FANCW, all of them are committed to remove the ICL and maintain genomic integrity through various types of DNA repair.…”

Section: Involvement Of Fa/brca Pathway In Dna Repairmentioning

confidence: 99%

“…In everyday life, we are exposed to sources of ICL inducing agents that can be both endogenous resulting from cellular metabolism or exogenous due to environmental, occupational or personal exposure habits. Some calculations suggest that in the steady state every cell could carry around 37,000 lesions per genome, and that ICLs account for approximately 1500 of these lesions, whose origin can be bi-functional chemicals related to formaldehyde, acetaldehyde, acrolein and in smaller proportions crotonaldehyde [4]. ICLs of exogenous origins are more difficult to assess since for all the agents with the capacity to induce them, only a small fraction (typically 1-5%) will be ICLs, while the majority of the induced DNA damage will be monoadducts or intrastrand crosslinks [5].…”

Section: Introductionmentioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Preprint

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Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, that cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired, and accumulation of toxic DNA double strand breaks occurs. In order to repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, that may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA and their segregation during cell division are the origin of subsequent aberrations like translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, that results in tissue attrition, selection of malignant clones and cancer onset. Moreover, the effect of the FA/BRCA pathway in germinal cells, evidenced by infertility in patients with FA attests of chromosomal instability and cell death also occurring in the germinal compartment.

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“…In everyday life, we are exposed to sources of ICL-inducing agents that can be both endogenous resulting from cellular metabolism or exogenous due to environmental, occupational or personal exposure habits. Some calculations suggest that in the steady state every cell could carry around 37,000 lesions per genome, and that ICLs account for approximately 1500 of these lesions, whose origin can be bi-functional chemicals related to formaldehyde, acetaldehyde, acrolein and in smaller proportions crotonaldehyde [ 4 ]. ICLs of exogenous origins are more difficult to assess since for all the agents with the capacity to induce them, only a small fraction (typically 1–5%) will be ICLs, while the majority of the induced DNA damage will be monoadducts or intrastrand crosslinks [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

García-de-Teresa

Rodríguez

Frı́as

2020

Genes

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Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.

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DNA-protein crosslink formation by endogenous aldehydes and AP sites

Cited by 48 publications

References 90 publications

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

The failure of two major formaldehyde catabolism enzymes (ADH5 and ALDH2) leads to partial synthetic lethality in C57BL/6 mice

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

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