Depletion of Dnmt1-associated protein 1 triggers DNA damage and compromises the proliferative capacity of hematopoietic stem cells.
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 gamma-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.
Koizumi
Tomoe
T
Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan.
Negishi
Masamitsu
M
Nakamura
Shunsuke
S
Oguro
Hideyuki
H
Satoh
Kaneshige
K
Ichinose
Masaharu
M
Iwama
Atsushi
A
D000818:Animals; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D018816:Genes, cdc / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C485852:Dmap1 protein, mouse; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53
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