Abstract
Dnmt1-associated protein 1 (Dmap1) is a core component of the NuA4 histone acetyltransferase complex and the Swr1 chromatin-remodeling complex. However, the cellular function of Dmap1 remains largely unknown. We previously reported that Dmap1 plays a crucial role in DNA repair and is indispensable for the maintenance of chromosomal integrity of mouse embryonic fibroblasts. In this study, we examined the role of Dmap1 in self-renewing HSCs. Dmap1-knockdown induced by Dmap1-specific shRNA severely compromised the proliferative capacity of HSCs in vitro and long-term repopulating capacity of HSCs in recipient mice. Dmap1-knockdown in HSCs triggered DNA damage as evident by the formation of foci of γ-H2AX and activated p53-dependent cell cycle checkpoints. Deletion of p53 in HSCs abrogated the activation of p53-dependent cell cycle checkpoints, but did not restore the HSC function impaired by the knockdown of Dmap1. These findings suggest that Dmap1 is essential for the maintenance of genomic integrity of self-renewing HSCs and highlight DNA damage as one of the major stresses causing HSC depletion.
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Acknowledgments
We thank Dr. Hiroyuki Miyoshi, RIKEN Bioresource Center for the CS-H1-shRNA-EF-1α-EGFP vector. This work was supported in part by Grants-in-Aid for Scientific Research (#20052009) and the Global COE Program (Global Center for Education and Research in Immune System Regulation and Treatment), MEXT, Japan, a Grant-in-aid for Core Research for Evolutional Science and Technology (CREST) from the Japan Science and Technology Corporation (JST) and a grant from the Takeda Science Foundation.
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Koizumi, T., Negishi, M., Nakamura, S. et al. Depletion of Dnmt1-associated protein 1 triggers DNA damage and compromises the proliferative capacity of hematopoietic stem cells. Int J Hematol 91, 611–619 (2010). https://doi.org/10.1007/s12185-010-0563-3
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DOI: https://doi.org/10.1007/s12185-010-0563-3