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FANCD2 Alleviates Physiologic Replication Stress in Fetal Liver HSC

Mochizuki-Kashio, M.; Yoon, Y. m.; Menna, T.; Grompe, M.; Kurre, P.

2020-10-01 developmental biology Community evaluation
10.1101/2020.09.30.320796 bioRxiv
Show abstract

Bone marrow failure (BMF) in Fanconi Anemia (FA) results from exhaustion of hematopoietic stem cells (HSC), but the physiological role of FA proteins in HSC pool integrity remains unknown. Herein we demonstrate that FANCD2, a core component of the FA pathway, counters replication stress during developmental HSC expansion in the fetal liver (FL). Rapid rates of proliferation and FANCD2 deficient result in excess RPA-coated ssDNA, and provoke pChk1 activation and Cdkn1a(p21) nuclear localization in fetal Fancd2-/- HSC. Checkpoint mediated S-phase delays induced by Cdkn1a(p21) are rescued by Tgf-{beta} inhibition, but pChk1 activation is further aggravated. Our observations reveal the mechanism and physiological context by which FANCD2 safeguards HSC pool formation during development.

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