Fanconi anemia and the underlying causes of genomic instability.
Fanconi anemia and the underlying causes of genomic instability.
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DOI：
10.1002/em.22358
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发表时间：
2020-08
影响因子：
2.8
通讯作者：
Kim H
中科院分区：
文献类型：
--
作者：
Rageul J;Kim H
Fanconi贫血(FA)是一种罕见的遗传性疾病，其特征是出生缺陷、进行性骨髓衰竭和易患癌症。这种毁灭性的疾病是由已知的22个FA基因中的任何一个基因的胚系突变引起的，其中基因产物主要负责DNA链间交链(ICL)的解析，ICL是一种通常由细胞毒性化疗药物形成的DNA损伤。然而，产生DNA ICL的内源性诱变剂的身份在很大程度上仍然难以捉摸。此外，DNA ICL是否确实是FA表型背后的主要原因仍是一个有争议的问题。最近的遗传学研究表明，天然产生的反应性醛是造血干细胞(HSCs)DNA损伤的主要来源，这意味着它们可能在基因组不稳定和FA中发挥作用。此外，新出现的证据表明，FA途径通过保护免受各种DNA复制压力而构成了对基因组的一般监测机制。因此，了解FA途径调控的DNA修复信号，以及FA病理生理学基础上的DNA损伤类型，对于FA和FA相关癌症的治疗至关重要。在这里，我们从FA介导的DNA修复和维持基因组完整性所触发的信号通路的背景下，对反应性醛、骨髓功能障碍和FA生物学之间的关系的最新进展进行综述。
Fanconi anemia (FA) is a rare genetic disorder, characterized by birth defects, progressive bone marrow failure, and a predisposition to cancer. This devastating disease is caused by germline mutations in any one of the 22 known FA genes, where the gene products are primarily responsible for the resolution of DNA interstrand cross-links (ICLs), a type of DNA damage generally formed by cytotoxic chemotherapeutic agents. However, the identity of endogenous mutagens that generate DNA ICLs remains largely elusive. In addition, whether DNA ICLs are indeed the primary cause behind FA phenotypes is still a matter of debate. Recent genetic studies suggest that naturally occurring reactive aldehydes are a primary source of DNA damage in hematopoietic stem cells (HSCs), implicating that they could play a role in genome instability and FA. In addition, emerging lines of evidence indicate that the FA pathway constitutes a general surveillance mechanism for the genome by protecting against a variety of DNA replication stresses. Therefore, understanding the DNA repair signaling that is regulated by the FA pathway, and the types of DNA lesions underlying the FA pathophysiology is crucial for the treatment of FA and FA-associated cancers. Here, we review recent advances in our understanding of the relationship between reactive aldehydes, bone marrow dysfunction, and FA biology in the context of signaling pathways triggered during FA-mediated DNA repair and maintenance of the genomic integrity.
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