@article{43d5193b75e640d7898b4d9d0f2ffe36,
title = "A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia",
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.",
keywords = "DNA damage, Fanconi anemia, bone marrow failure, differentiation, formaldehyde, hematopoiesis, transcription reprogramming",
author = "Xi Shen and Rui Wang and Kim, {Moon Jong} and Qianghua Hu and Hsu, {Chih Chao} and Jun Yao and Naeh Klages-Mundt and Yanyan Tian and Erica Lynn and Brewer, {Thomas F.} and Yilei Zhang and Banu Arun and Boyi Gan and Michael Andreeff and Shunichi Takeda and Junjie Chen and Park, {Jae il} and Xiaobing Shi and Chang, {Christopher J.} and Jung, {Sung Yun} and Jun Qin and Lei Li",
note = "Funding Information: We thank Weidong Wang (NIA, NIH) for providing FANCL antibodies, Lee Zou (MGH, Harvard Medical School) for providing the S9.6 antibody and technical advice, and Margaret (Peggy) Goodell (Baylor College of Medicine) for technical discussions on HSCs. Founding source include CA190635 and CA193124-Project 3 (to L.L.), ES 4705 and ES 28096 (to C.J.C.), CA204020 (to X. Shi), CA157448 (to J.C.), and Cancer Prevention and Research Institute of Texas Grant RP160667 (to J.C. and L.L.). C.J.C. is an Investigator with the Howard Hughes Medical Institute and T.F.B. was partially supported by a Chemical Biology Training Grant from the NIH ( T32 GM066698 ). This research was partly supported by the Fundamental Research Funds for the Central Universities . The M.D. Anderson Flow Cytometry, DNA Sequencing, and Characterized Cell Line core facilities are supported by the National Cancer Institute Cancer Center Support Grant CA016672 . Funding Information: We thank Weidong Wang (NIA, NIH) for providing FANCL antibodies, Lee Zou (MGH, Harvard Medical School) for providing the S9.6 antibody and technical advice, and Margaret (Peggy) Goodell (Baylor College of Medicine) for technical discussions on HSCs. Founding source include CA190635 and CA193124-Project 3 (to L.L.), ES 4705 and ES 28096 (to C.J.C.), CA204020 (to X. Shi), CA157448 (to J.C.), and Cancer Prevention and Research Institute of Texas Grant RP160667 (to J.C. and L.L.). C.J.C. is an Investigator with the Howard Hughes Medical Institute and T.F.B. was partially supported by a Chemical Biology Training Grant from the NIH (T32 GM066698). This research was partly supported by the Fundamental Research Funds for the Central Universities. The M.D. Anderson Flow Cytometry, DNA Sequencing, and Characterized Cell Line core facilities are supported by the National Cancer Institute Cancer Center Support Grant CA016672. X. Shen, R.W. M.J.K. Q.H. C.-C.H. N.K.-M. Y.T. Y.Z. and E.L. performed experiments. J.Y. analyzed data. S.Y.J. performed mass spectrometry experiment and analyzed data. T.F.B. and C.J.C. generated reagents for the study. J.Y. performed ChIP-seq data analyses. B.A. B.G. M.A. S.T. J.-I.P. C.J.C. J.C. X. Shi, J.Q. and L.L. designed and interpreted the experiments and wrote the manuscript. The authors declare no conflict of interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = dec,
day = "17",
doi = "10.1016/j.molcel.2020.11.040",
language = "English (US)",
volume = "80",
pages = "1013--1024.e6",
journal = "Molecular cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}