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Regulation of epigenetic modifications of chromatin by the VRK1 kinase

AuthorsSalzano, Marcella ; Campillo-Marcos, Ignacio ; Moura, David S.; Lazo, Pedro A.
Issue Date2015
CitationEACR Conference Series (2015)
AbstractChromatin organization is regulated by covalent modifications of histones such as acetylation or methylation in specific residues, which can be regulated by phosphorylations. VRK1 is a nuclear Ser-Thr kinase implicated in many nuclear processes, such as proliferation, cell cycle or DNA Damage Repair (DDR). VRK1 is present in the chromatin fraction and is able to interact and phosphorylate H2AX in Ser139 after DNA Damage induced by irradiation, and also phosphorylates histone H3 in Thr3. In this work we have studied the role of human VRK1 Ser-Thr in the control of DNA damage response to IR and the role of specific acetylation and methylation of histones. We have shown that VRK1 is necessary for a proper formation of 53BP1 and γH2AX foci formation at double strand-breaks induced by ionizing radiation in and ATM-independent manner. DSB imply a local relaxation of chromatin and therefore it is likely that it might alter the modifications of histones. Fist we tested if acetylation is required for formation of DSB foci, and whether these acetylations require VRK1. The depletion of VRK1 by siRNA i affected the acetylation of H3 in Lys14 and Lys9 and also the H4 acetylation in Lys16, important markers of transcriptional activation. In contrast, siVRK1 enhanced the H3 methylation in Lys9 (a gene repressor marker) but not in Lys4 (transcriptional activator residue), confirming the role of VRK1 in positively mediating gene transcription. Also we have determined if manipulation of VRK1 levels can alter the tumour cell sensitivity to drugs currently used in clinical trials that target histone acetylation or methylation. Pharmacological inhibition of histone acetyl transferases (HATs) or VRK1 depletion did not rescue H3K9 and H4K16 acetylations, indicating that VRK1 is a regulator of HATs. We conclude that VRK1 regulates epigenetic mechanisms and has a role in chromatin condensation.
DescriptionResumen del póster presentado a la European Association for Cancer Research (EACR) Conference on Basic Epigenetic Mechanisms in Cancer, celebrada en Berlin (Alemania) del 8 al 11 de noviembre de 2015.
Appears in Collections:(IBMCC) Comunicaciones congresos
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