A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
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DNA 损伤激增与范可尼贫血中的转录重编程和造血缺陷有关。
DOI：
10.1016/j.molcel.2020.11.040
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发表时间：
2020-12-17
期刊：
影响因子：
16
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Shen X;Wang R;Kim MJ;Hu Q;Hsu CC;Yao J;Klages-Mundt N;Tian Y;Lynn E;Brewer TF;Zhang Y;Arun B;Gan B;Andreeff M;Takeda S;Chen J;Park JI;Shi X;Chang CJ;Jung SY;Qin J;Li L
DNA交联修复受损导致范可尼贫血（FA），其特征在于由DNA损伤反应缺陷引起的疾病中骨髓衰竭和全血细胞减少的独特表现。作为一种生殖系疾病，为什么造血系统受到特别影响还没有完全理解。我们发现，在造血分化过程中的转录重编程导致超负荷的遗传毒性应激，这导致流产的分化和消耗的FA突变祖细胞。DNA损伤的发生最有可能是由甲醛引起的，甲醛是转录调节过程中氧化蛋白质去甲基化的一种专性副产物。我们的研究结果表明，快速和广泛的转录重编程与造血分化的基因组稳定性和细胞活力的FA途径的情况下构成了重大威胁。分化与DNA损伤积累之间的联系揭示了基因组瘢痕形成的新机制，对于探索治疗FA患者的抗再生障碍性贫血疗法至关重要。
Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.
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DOI：
10.1016/s0165-1218(96)90043-9
发表时间：
1996-07-10
期刊：
MUTATION RESEARCH-GENETIC TOXICOLOGY
影响因子：
--
作者：
Costa, M;Zhitkovich, A;Bogdanffy, M
通讯作者：
Bogdanffy, M
DOI：
10.1056/nejmra0809889
发表时间：
2010-05-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
D'Andrea AD
通讯作者：
D'Andrea AD
影响因子：
64.5
作者：
Duxin JP;Dewar JM;Yardimci H;Walter JC
通讯作者：
Walter JC
影响因子：
8.8
作者：
Huang Y;Leung JW;Lowery M;Matsushita N;Wang Y;Shen X;Huong D;Takata M;Chen J;Li L
通讯作者：
Li L
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.