Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Garaycoechea, Juan I.; Crossan, Gerry P.; Langevin, Frédéric; Mulderrig, Lee; Louzada, Sandra; Yang, Fengtang; Guilbaud, Guillaume; Park, Naomi; Roerink, Sophie F.; Nik-Zainal, Serena; Stratton, Michael R.; Patel, Ketan

doi:10.1038/nature25154

Cited by 323 publications

(313 citation statements)

References 46 publications

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“…However, because of the reactivity of its aldehyde group PLP can be involved in other, unwanted reactions with macromolecules within the cell (a form of aldehyde or carbonyl stress) analogous to the unwanted reactions of reactive oxygen species. Reactions of PLP with amino groups of proteins can alter their structure and at concentrations of 10 to 100 μM inhibit enzyme activity and aldehydes can damage DNA leading to mutagenesis . PLP can also react with small molecules including sulphydryl compounds such as cysteine resulting in the formation of thiazoliodines and with sulfite producing a sulphonate.…”

Section: Reactivitymentioning

confidence: 99%

“…Reactions of PLP with amino groups of proteins can alter their structure 5 and at concentrations of 10 to 100 μM inhibit enzyme activity 6 and aldehydes can damage DNA leading to mutagenesis. 7 PLP can also react with small molecules 8,9 including sulphydryl compounds such as cysteine resulting in the formation of thiazoliodines 10 and with sulfite producing a sulphonate. The aldehyde group of PLP can also react, via Knoevenagel condensation, with Δ 1 -pyrroline 5-carboxylate and Δ 1 -piperideine 6-carboxylate.…”

Section: Reactivitymentioning

confidence: 99%

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Disorders affecting vitamin B₆ metabolism

Wilson¹,

Plecko²,

Mills³

et al. 2019

J of Inher Metab Disea

169

186

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Vitamin B6 is present in our diet in many forms, however, only pyridoxal 5′‐phosphate (PLP) can function as a cofactor for enzymes. The intestine absorbs nonphosphorylated B6 vitamers, which are converted by specific enzymes to the active PLP form. The role of PLP is enabled by its reactive aldehyde group. Pathways reliant on PLP include amino acid and neurotransmitter metabolism, folate and 1‐carbon metabolism, protein and polyamine synthesis, carbohydrate and lipid metabolism, mitochondrial function and erythropoiesis. Besides the role of PLP as a cofactor B6 vitamers also play other cellular roles, for example, as antioxidants, modifying expression and action of steroid hormone receptors, affecting immune function, as chaperones and as an antagonist of Adenosine‐5'‐triphosphate (ATP) at P2 purinoceptors. Because of the vital role of PLP in neurotransmitter metabolism, particularly synthesis of the inhibitory transmitter γ‐aminobutyric acid, it is not surprising that various inborn errors leading to PLP deficiency manifest as B6‐responsive epilepsy, usually of early onset. This includes pyridox(am)ine phosphate oxidase deficiency (a disorder affecting PLP synthesis and recycling), disorders affecting PLP import into the brain (hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects), a disorder of an intracellular PLP‐binding protein (PLPBP, previously named PROSC) and disorders where metabolites accumulate that inactivate PLP, for example, ALDH7A1 deficiency and hyperprolinaemia type II. Patients with these disorders can show rapid control of seizures in response to either pyridoxine and/or PLP with a lifelong dependency on supraphysiological vitamin B6 supply. The clinical and biochemical features of disorders leading to B6‐responsive seizures and the treatment of these disorders are described in this review.

show abstract

Section: Reactivitymentioning

confidence: 99%

Section: Reactivitymentioning

confidence: 99%

Disorders affecting vitamin B₆ metabolism

Wilson¹,

Plecko²,

Mills³

et al. 2019

J of Inher Metab Disea

169

186

View full text Add to dashboard Cite

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“…Chronic alcohol consumption in humans causes various cancers [32][33][34] . The causative agent for the devastating effects of alcohol consumption is found to be acetaldehyde and thus it is demonstrated as a genotoxic and teratogenic agent in mice and humans 34 .…”

Section: Aa-trna Is the First Target To Get Modified By Acetaldehydementioning

confidence: 99%

Recruitment of Archaeal DTD is a Key Event in the Emergence of Land Plants

Mazeed

Singh

Kumar

et al. 2020

Preprint

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Land plant evolution is a major leap in the history of life that took place during the Neoproterozoic Era (~800 Mya). Charophyceae, a class of rhyzophytic green algae emerged as a land plant with innovations in biochemical, cytological and developmental adaptations and played a crucial role in establishing life on the land 1,2 . One such striking architectural innovation is "root" that experience harsh environmental assaults such as floods, waterlogging and therefore is the epicentre for anaerobic fermentation, which produces toxic acetaldehyde 3 . Here, we show that such produced acetaldehyde makes N-ethyl-adducts on a central component of translation machinery aa-tRNA. The Plant kingdom is unique among life forms in possessing two chirality-based proofreading systems represented by Daminoacyl-tRNA deacylases (DTD1 and DTD2), derived from Bacteria and Archaea 4 . We identified a unique role of archaeal derived chiral proofreading module DTD2 that selectively deacylates N-ethyl-D-aminoacyl-tRNAs (NEDATs) in plants. NEDAT deacylase function is exclusive to DTD2, as no other proofreading modules with similar substrates like canonical DTD1 and peptidyl-tRNA hydrolase (PTH) can clear NEDATs. Thus, the study elucidates the cause of hypersensitivity of DTD2 knockout plants for both ethanol and acetaldehyde. We further show NEDAT elimination is rooted in Archaea which possess the biosynthesis machinery for ethanol fermentation similar to plants. While absent in other algal branches, DTD2 can be identified in plants from land plant ancestors-Charophytes onwards. DTD2 is the only gene that has only archaeal origin among the genes ascribed for architectural and genomic innovations that happened in the land plant ancestors. The work has uncovered an important gene transfer event from methanogenic archaea to the charophytes in the oldest terrestrial ecosystem bog that contains excess of D-amino acids and deprived of oxygen. 3 Plants being sedentary in their lifestyle are dependent on roots for their nourishment and root has to survive in the oxygen-deprived environment of soil. The soil also being enriched with D-amino acids makes roots clutched with inescapable stress of D-amino acids compounded with anaerobic stress. The presence of D-amino acids in plants is inevitable and play vital roles in plant physiology such as the development of the pollen tube and also act as a major nitrogen source 5 . On the contrary, D-amino acids also cause cellular toxicity by generating Daminoacyl-tRNAs (D-aa-tRNAs) which arrests free tRNA pool from translation. Removal of mischarged D-amino acids from D-aa-tRNAs is termed as chiral proofreading 6 that enables the perpetuation of homochirality in the cellular proteome 7 . D-amino acid editing modules are universally conserved; D-aminoacyl-tRNA deacylase 1 (DTD1) is present in both Bacteria and Eukaryotes and DTD2 is in Archaea and plants 4 . Plants are the only organisms that possess both the evolutionarily distinct chiral proofreading modules DTD1 and DTD2 8,9 . Surprisingly, DTD2 knock out...

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“…27 Micronuclei are extra nuclear segments of chromatin that is one marker of genetic instability and associated with tumor predisposition. 28 To test whether the ANKLE inhibits the development of CRC through a similar mechanism, we first knocked down the expression of ANKLE1 in CRC cells and then tested the proportion of micronucleated cells. The results showed that depletion of ANKLE1 significantly increased the frequency of the micronucleated cells formation in SW480 and HCT116 cell lines ( Figs.…”

Section: The Ankle1[a] Reduced Genomic Instability Of Crc Cellsmentioning

confidence: 99%

ANKLE1 N⁶‐Methyladenosine‐related variant is associated with colorectal cancer risk by maintaining the genomic stability

Tian

Ying

et al. 2019

Intl Journal of Cancer

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The N 6 -Methyladenosine (m 6 A) modification plays an important role in many biological processes, especially tumor development. However, little is still known about how it affects colorectal cancer (CRC) carcinogenesis. Here, we first systematically investigate the association of variants related to m 6 A modification with the CRC risk in 1,062 CRC cases and 2,184 controls by using our exome-wide association data and followed by two replication sets including 7,341 CRC cases and 7,902 controls. The variant rs8100241 located in ANKLE1 was significantly associated with CRC risk (odds ratio = 0.88, 95% confidence interval = 0.84-0.92, p = 4.85 × 10 −8 ) in 8,403 cases and 10,086 controls. This variant was previously identified to be associated with the susceptibility of breast cancer with BRCA1 mutation triple negative breast cancer. Further functional analysis indicated that overexpression of the rs8100241[A] allele significantly increased the ANKLE1 m 6 A level and facilitated the ANKLE1 protein expression compared to that of rs8100241[G] allele. We further found the ANKLE1 m 6 A modification was catalyzed by the "writer" complex (METTL3, METTL14, or WTAP) and recognized by the "reader" YTHDF1. Mechanistically, we found that the ANKLE1 functions as a potential tumor suppressor that inhibits cell proliferation and facilitates the genomic stability. An elevated frequency of micronucleated cells, increased cell proliferation, and colony formation ability were observed when ANKLE1 knockdown. Our study illustrated that the germline missense variant can increase CRC risk by influencing ANKLE1 m 6 A level, highlighting a clinical potential of variantsassociated m 6 A modification as a risk marker for CRC prevention.*J.T. and P.Y. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

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Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Cited by 323 publications

References 46 publications

Disorders affecting vitamin B₆ metabolism

Disorders affecting vitamin B₆ metabolism

Recruitment of Archaeal DTD is a Key Event in the Emergence of Land Plants

ANKLE1 N⁶‐Methyladenosine‐related variant is associated with colorectal cancer risk by maintaining the genomic stability

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Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells

Cited by 323 publications

References 46 publications

Disorders affecting vitamin B6 metabolism

Disorders affecting vitamin B6 metabolism

Recruitment of Archaeal DTD is a Key Event in the Emergence of Land Plants

ANKLE1 N6‐Methyladenosine‐related variant is associated with colorectal cancer risk by maintaining the genomic stability

Contact Info

Product

Resources

About

Disorders affecting vitamin B₆ metabolism

Disorders affecting vitamin B₆ metabolism

ANKLE1 N⁶‐Methyladenosine‐related variant is associated with colorectal cancer risk by maintaining the genomic stability