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Publication Detail

Title: A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Authors: Shen, Xi; Wang, Rui; Kim, Moon Jong; Hu, Qianghua; Hsu, Chih-Chao; Yao, Jun; Klages-Mundt, Naeh; Tian, Yanyan; Lynn, Erica; Brewer, Thomas F; Zhang, Yilei; Arun, Banu; Gan, Boyi; Andreeff, Michael; Takeda, Shunichi; Chen, Junjie; Park, Jae-Il; Shi, Xiaobing; Chang, Christopher J; Jung, Sung Yun; Qin, Jun; Li, Lei

Published In Mol Cell, (2020 12 17)

Abstract: 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.

PubMed ID: 33338401 Exiting the NIEHS site

MeSH Terms: Cell Differentiation/drug effects*; Cellular Reprogramming/genetics*; DNA Damage/drug effects; DNA Repair/genetics; Fanconi Anemia/blood; Fanconi Anemia/genetics*; Fanconi Anemia/pathology; Formaldehyde/metabolism; Formaldehyde/toxicity*; Gene Expression Regulation, Developmental/drug effects; Gene Expression Regulation, Developmental/genetics; Genomic Instability/genetics; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells/drug effects; Humans; K562 Cells; Transcription, Genetic

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