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A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
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.
  • Shen X; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Wang R; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Kim MJ; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Hu Q; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Hsu CC; Department of Epigenetics and Molecular Carcinogenesis, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Yao J; Department of Molecular Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Klages-Mundt N; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Tian Y; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Lynn E; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Brewer TF; Department of Chemistry, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Zhang Y; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Arun B; Department of Breast Medical Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Gan B; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Andreeff M; Department of Leukemia, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Takeda S; Department of Radiation Biology, Kyoto University, 606-8501 Kyoto, Japan.
  • Chen J; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Park JI; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Shi X; Department of Epigenetics and Molecular Carcinogenesis, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA.
  • Chang CJ; Department of Chemistry, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  • Jung SY; Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
  • Qin J; Department of Biochemistry, Baylor College of Medicine, Houston, TX 77030, USA.
  • Li L; Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA; Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. Electronic address: leili852002@yahoo.com.
Mol Cell ; 80(6): 1013-1024.e6, 2020 12 17.
Article en En | MEDLINE | ID: mdl-33338401
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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Diferenciación Celular / Reprogramación Celular / Anemia de Fanconi / Formaldehído Límite: Humans Idioma: En Año: 2020 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Diferenciación Celular / Reprogramación Celular / Anemia de Fanconi / Formaldehído Límite: Humans Idioma: En Año: 2020 Tipo del documento: Article