Endogenous DNA damage and its repair during haematopoiesis

造血过程中内源性DNA损伤及其修复

• 批准号: MC_UU_00029/1
• 负责人: Ketan Patel
• 金额: $ 595.18万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00029%2F1
• 关键词: Endogenous; DNA; damage; its; repair

Endogenous DNA damage is an important and dominant cause for the accumulation of mutations in all organisms. This can be seen in the mutation signatures associated with cells obtained from aged animals and in most cancers. The established factors and processes that cause endogenous DNA damage are oxygen, water, structured DNA and DNA replication and transcription. However, a fundamental question is whether there are other factors that are prevalent drivers for endogenous DNA damage and DNA repair pathways mitigate against such damage. Our research has identified that simple aldehydes such as formaldehyde and acetaldehyde are produced in our cells that can cause DNA damage possibly through the formation of DNA crosslinks. We uncovered that a two-tier protection mechanism (aldehyde detoxification and DNA repair) ensure that these metabolites do not cause DNA damage and mutations.

内源性 DNA 损伤是所有生物体突变积累的重要且主导原因。这可以从与从老年动物和大多数癌症中获得的细胞相关的突变特征中看出。造成内源性 DNA 损伤的既定因素和过程是氧气、水、结构化 DNA 以及 DNA 复制和转录。然而，一个基本问题是是否还有其他因素是内源性 DNA 损伤的普遍驱动因素，而 DNA 修复途径是否可以减轻这种损伤。我们的研究发现，我们的细胞中会产生甲醛和乙醛等简单醛，这些醛可能通过形成 DNA 交联而导致 DNA 损伤。我们发现，两层保护机制（醛解毒和 DNA 修复）可确保这些代谢物不会导致 DNA 损伤和突变。

项目成果

Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.

• DOI: 10.1016/j.molcel.2023.05.035
• 发表时间: 2023-07-20
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Wang M;Brandt LTL;Wang X;Russell H;Mitchell E;Kamimae-Lanning AN;Brown JM;Dingler FA;Garaycoechea JI;Isobe T;Kinston SJ;Gu M;Vassiliou GS;Wilson NK;Göttgens B;Patel KJ
• 通讯作者: Patel KJ