A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.
Cell Differentiation
/ drug effects
Cellular Reprogramming
/ genetics
DNA Damage
/ drug effects
DNA Repair
/ genetics
Fanconi Anemia
/ blood
Formaldehyde
/ metabolism
Gene Expression Regulation, Developmental
/ drug effects
Genomic Instability
/ genetics
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells
/ drug effects
Humans
K562 Cells
Transcription, Genetic
DNA damage
Fanconi anemia
bone marrow failure
differentiation
formaldehyde
hematopoiesis
transcription reprogramming
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 12 2020
17 12 2020
Historique:
received:
30
07
2019
revised:
26
07
2020
accepted:
23
11
2020
entrez:
18
12
2020
pubmed:
19
12
2020
medline:
16
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33338401
pii: S1097-2765(20)30840-6
doi: 10.1016/j.molcel.2020.11.040
pmc: PMC8600940
mid: NIHMS1653390
pii:
doi:
Substances chimiques
Formaldehyde
1HG84L3525
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1013-1024.e6Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES028096
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA190635
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA157448
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204020
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA193124
Pays : United States
Organisme : NIEHS NIH HHS
ID : P42 ES004705
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM066698
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no conflict of interests.
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