Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Faithful control of cell cycle checkpoint and DNA repair contributes to prevent the cells from chromosomal instability and tumorigenesis. Dnmt1-associated protein 1 (Dmap1), a component of the NuA4 histone acetyltransferase complex, was originally identified as an interacting molecule with DNMT1 which co-localizes with PCNA at DNA replication foci. However, its role in cellular functions remains largely unknown. Here we show that Dmap1 knockdown in mouse embryonic fibroblasts (MEFs) lead to spontaneous double-strand breaks (DSBs), resulting in growth arrest because of p53-dependent cell cycle checkpoint activation. Deletion of both Dmap1 and p53 in MEFs synergized towards enhanced generation of DSBs, chromosomal abnormalities and tumor development in mice. Notably, we found that, on DNA damage, Dmap1 was recruited to the damaged sites to form complexes with gamma-H2AX and replication factors, including Pcna. Depletion of Dmap1 in MEFs abrogated the stable accumulation of Pcna at the DNA damaged sites. Furthermore, the re-introduction of Dmap1 mutants with a reduced capacity to bind Pcna failed to ameliorate the impaired DNA repair in Dmap1-depleted cells. These findings indicate that Dmap1 is required to involve Pcna in DNA repair. Together, Dmap1 plays a crucial role in DNA repair, and is indispensable for the maintenance of chromosomal integrity.
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PMID:Dmap1 plays an essential role in the maintenance of genome integrity through the DNA repair process. 1984 71

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.
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PMID:Depletion of Dnmt1-associated protein 1 triggers DNA damage and compromises the proliferative capacity of hematopoietic stem cells. 2038 33