ALDH2 mutations and defense against genotoxic aldehydes in cancer and inherited bone marrow failure syndromes

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2024-07-01 DOI:10.1016/j.mrfmmm.2024.111870

Anthony Yiu-Ho Woo, Lina Jia

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Abstract

Reactive aldehydes, for instance, formaldehyde and acetaldehyde, are important endogenous or environmental mutagens by virtue of their abilities to produce a DNA lesion called interstrand crosslink (ICL). Aldehyde-metabolizing enzymes such as aldehyde dehydrogenases (ALDHs) and the Fanconi anemia (FA) pathway constitute the main defense lines against aldehyde-induced genotoxicity. Biallelic mutations of genes in any one of the FA complementation groups can impair the ICL repair mechanism and cause FA, a heterogeneous disorder manifested by bone marrow failure (BMF), congenital abnormality and a strong predisposition to cancer. The defective ALDH2 polymorphism rs671 (ALDH2*2) is a known risk and prognostic factor for alcohol drinking-associated cancers. Recent studies suggest that it also promotes BMF and cancer development in FA, and its combination with alcohol dehydrogenase 5 (ADH5) mutations causes aldehyde degradation deficiency syndrome (ADDS), also known by its symptoms as aplastic anemia, mental retardation, and dwarfism syndrome. ALDH2*2 and another pathogenic variant in the alcohol-metabolizing pathway, ADH1B1*1, is prevalent among East Asians. Also, other ALDH2 genotypes with disease-modifying potentials have lately been identified in different populations. Therefore, it would be appropriate to summarize current knowledge of genotoxic aldehydes and defense mechanisms against them to shed new light on the pathogenic effects of ALDH2 variants together with other genetic and environmental modifiers on cancer and inherited BMF syndromes. Lastly, we also presented potential treatment strategies for FA, ADDS and cancer based on the manipulation of aldehyde-induced genotoxicity.

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癌症和遗传性骨髓衰竭综合征中的 ALDH2 基因突变和对基因毒性醛的防御。

反应性醛（如甲醛和乙醛）是重要的内源性或环境诱变剂，因为它们能够产生一种称为链间交联（ICL）的 DNA 病变。醛代谢酶（如醛脱氢酶（ALDHs））和范可尼贫血症（FA）途径是抵御醛诱导的遗传毒性的主要防线。FA互补组中任何一个基因的双倍突变都会损害ICL修复机制，导致FA这种表现为骨髓衰竭（BMF）、先天畸形和极易罹患癌症的异质性疾病。已知有缺陷的 ALDH2 多态性 rs671（ALDH2*2）是饮酒相关癌症的风险和预后因素。最近的研究表明，它还会促进 BMF 和 FA 中癌症的发生，它与酒精脱氢酶 5（ADH5）突变结合会导致醛降解缺陷综合征（ADDS），该综合征也被称为再生障碍性贫血、智力迟钝和侏儒综合征。ALDH2*2 和酒精代谢途径中的另一种致病变体 ADH1B1*1 在东亚人中很普遍。此外，最近还在不同人群中发现了其他具有改变疾病潜能的 ALDH2 基因型。因此，我们有必要总结一下目前有关基因毒性醛类及其防御机制的知识，以揭示 ALDH2 基因变异及其他遗传和环境因素对癌症和遗传性 BMF 综合征的致病作用。最后，我们还介绍了在控制醛诱导的遗传毒性的基础上治疗 FA、ADDS 和癌症的潜在策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.