A surge of DNA damage links transcriptional reprogramming and hematopoietic deficit in Fanconi anemia

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 recessive 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. The onset of DNA damage 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.