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20-kDa FANCA-associated protein(FAAP20)is a recently identified protein that associates with the Fanconi anemia(FA)core complex component,FANCA.FAAP20 contains a conserved ubiquitin binding zinc-finger domain and plays critical roles in the FA-BRCA pathway of DNA repair and genome maintenance.The function of FAAP20 in animals has not been explored.Here,we report that deletion of Faap20 in mice led to a mild FA-like phenotype with defects in the reproductive and hematopoietic systems.Specifically.hematopoietic stem and progenitor cells(HSPCs)from Faap202/2 mice showed defects in long-term multilineage reconstitution in lethally irradiatzed2 recinient mice,with milder phenotype as compared to HSPCs from Fanca2/2 0r Fancc2/Faap202/2 mice are susceptible to mitomycin C(MMC)-induced pancytopenia.Thatis,acute MMC stress induced a significant progenitor loss especially the erythroid progenitors and megakaryoocyte erythrocyte progenitors in Faap202/2 mice.Furthermore,Faap202/2 HSPCs displayed aberrant cell cycle pattern during chronic MMC treatment.Finally.using Faap202/2 Fanca2/2 double-knockout mice,we demonstrated a possible dominant effect of FANCA in the interaction between FAAP20 and FANCA.This novel Faap20 mouse model may be valuable in studying the regulation ofthe FA pathway during bone marrow failure progress in FA patients.STEM C ELLS 2015;33:2320-2330.