Genome-wide mapping of genomic DNA damage: methods and implications.
Genome-wide mapping of genomic DNA damage: methods and implications.
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DOI：
10.1007/s00018-021-03923-6
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Cooke MS
中科院分区：
文献类型：
--
作者：
Amente S;Scala G;Majello B;Azmoun S;Tempest HG;Premi S;Cooke MS
外部和内部环境的暴露会导致基因组 DNA 的改变，这与许多疾病的病因有关，包括癌症、心血管、肺部和神经退行性疾病以及衰老。然而，将损伤的存在与细胞功能和发病机制的影响联系起来的精确机制尚不清楚。特定形式损伤的基因组定位对于理解这一过程可能提供大量信息，因为下游事件（例如突变、微卫星不稳定性、甲基化和基因表达改变）对细胞功能的影响将是位置性的——关键位置的事件将产生最大的影响。然而，直到最近，评估 DNA 损伤的方法只能在没有位置信息的情况下确定基因组位置的总体损伤。 “绘制 DNA 加合物组学”技术描述了将各种形式的 DNA 损伤绘制到核和线粒体基因组特定位置的分子方法。我们建议，将此信息与其他全基因组数据（例如特定基因毒素的突变热点、肿瘤特异性突变模式以及非癌性病变（如痣）、癌前病变（如息肉）和肿瘤中的染色质组织和转录活性）进行综合比较，将提高我们对环境毒素如何导致癌症的理解。对非癌症疾病采用类似的方法，包括开发针对 DNA 损伤的其他细胞结果的全基因组检测，将更广泛地提高我们对 DNA 损伤在发病机制中的作用的理解。
Exposures from the external and internal environments lead to the modification of genomic DNA, which is implicated in the cause of numerous diseases, including cancer, cardiovascular, pulmonary and neurodegenerative diseases, together with ageing. However, the precise mechanism(s) linking the presence of damage, to impact upon cellular function and pathogenesis, is far from clear. Genomic location of specific forms of damage is likely to be highly informative in understanding this process, as the impact of downstream events (e.g. mutation, microsatellite instability, altered methylation and gene expression) on cellular function will be positional—events at key locations will have the greatest impact. However, until recently, methods for assessing DNA damage determined the totality of damage in the genomic location, with no positional information. The technique of “mapping DNA adductomics” describes the molecular approaches that map a variety of forms of DNA damage, to specific locations across the nuclear and mitochondrial genomes. We propose that integrated comparison of this information with other genome-wide data, such as mutational hotspots for specific genotoxins, tumour-specific mutation patterns and chromatin organisation and transcriptional activity in non-cancerous lesions (such as nevi), pre-cancerous conditions (such as polyps) and tumours, will improve our understanding of how environmental toxins lead to cancer. Adopting an analogous approach for non-cancer diseases, including the development of genome-wide assays for other cellular outcomes of DNA damage, will improve our understanding of the role of DNA damage in pathogenesis more generally.
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