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.

范可尼贫血（Fanconi anemia, FA）由DNA交联修复缺陷引发，是DNA损伤应答缺陷相关疾病中，以骨髓衰竭和全血细胞减少为独特表型的一类病症。作为一种隐性生殖系遗传病，为何造血系统层级会受到特异性累及，目前尚未完全阐明。本研究发现，造血分化过程中的转录重编程会导致遗传毒性应激负荷过载，进而引发FA突变祖细胞的分化阻滞与耗竭。此类DNA损伤的诱因极可能为甲醛——这是转录调控过程中氧化性蛋白质去甲基化的必然副产物。本研究结果证实，在FA通路缺失的情况下，与造血分化相关的快速且大规模的转录重编程，会对基因组稳定性与细胞存活构成严重威胁。造血分化与DNA损伤蓄积之间的关联，揭示了一种全新的基因组瘢痕形成机制，同时为探索针对FA患者的再生障碍性贫血治疗方案提供了关键理论依据。