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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  Faap20 −  /  −   mice showed defects in long‐term multilineage reconstitution in lethally irradiated recipient mice, with milder phenotype as compared to HSPCs from  Fanca −  /  −   or  Fancc −  /  −   mice.  Faap20 −  /  −   mice are susceptible to mitomycin C (MMC)‐induced pancytopenia. That is, acute MMC stress induced a significant progenitor loss especially the erythroid progenitors and megakaryocyte–erythrocyte progenitors in  Faap20 −  /  −   mice. Furthermore,  Faap20 −  /  −   HSPCs displayed aberrant cell cycle pattern during chronic MMC treatment. Finally, using  Faap20 −  /  −  Fanca −  /  −   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 of the FA pathway during bone marrow failure progress in FA patients. S tem  C ells   2015;33:2320–2330

Loss of Faap20 Causes Hematopoietic Stem and Progenitor Cell Depletion in Mice Under Genotoxic Stress