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引用次数: 0
摘要
衰老是分子和生理过程中复杂而动态的变化,与许多疾病相关,部分原因是遗传不稳定性增加。预计到 2050 年,老龄化人口将翻一番,这表明迫切需要更好地了解老龄化与年龄相关疾病之间的关系。重复 DNA 元素是遗传不稳定性的内在来源,已被发现与人类癌症基因组中的突变热点共存。在这项研究中,我们利用与癌症相关的人类 c-MYC 基因中的 H-DNA 形成镜像重复序列,探讨了衰老与 DNA 重复介导的体内遗传不稳定性之间的关系。利用独特的突变报告小鼠模型,我们观察到衰老对 H-DNA 诱导的遗传不稳定性的组织特异性影响,突变频率在脾组织中增加,而在睾丸组织中保持不变。对突变频谱的分析表明,大缺失突变是H-DNA诱导突变增加的主要原因,而在衰老的脾脏组织中,H-DNA结构的裂解活性增加也证明了这一点。我们的研究结果表明,衰老对重复介导的癌症相关突变具有不同的组织特异性影响,这为了解衰老与癌症之间的复杂关系提供了启示。
Tissue-Specific Effects of Aging on Repeat-Mediated Mutation Hotspots In Vivo.
Aging constitutes complex and dynamic alterations in molecular and physiological processes and is associated with numerous disorders, in part due to increased genetic instability. The aging population is projected to double by 2050, underscoring the urgent need to better understand the relationships between aging and age-related disorders. Repetitive DNA elements are intrinsic sources of genetic instability and have been found to co-localize with mutation hotspots in human cancer genomes. In this study, we explored the relationship between aging and DNA repeat-mediated genetic instability in vivo using an H-DNA-forming mirror-repeat sequence from the cancer-associated human c-MYC gene. Utilizing a unique mutation-reporter mouse model, we observed tissue-specific effects of aging on H-DNA-induced genetic instability, with mutation frequencies increasing in spleen tissues and remaining unchanged in testis tissues. Analysis of the mutation spectra revealed large deletion mutations as the primary contributor to increasing H-DNA-induced mutations, supported by increased cleavage activity of H-DNA structures in aged spleen tissues. Our findings demonstrate that aging has distinct tissue-specific effects on repeat-mediated, cancer-associated mutations, providing insights into the complex relationship between aging and cancer.
BiomoleculesBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍:
Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.