VRK1 Phosphorylates Tip60/KAT5 and Is Required for H4K16 Acetylation in Response to DNA Damage
García-González, Raúl (Instituto de Investigación Biomédica de Salamanca)
Morejón-García, Patricia (Instituto de Investigación Biomédica de Salamanca)
Campillo-Marcos, Ignacio (Instituto de Investigación Biomédica de Salamanca)
Salzano, Marcella (Hospital Universitari Vall d'Hebron)
Lazo, Pedro A. (Instituto de Investigación Biomédica de Salamanca)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	Dynamic remodeling of chromatin requires epigenetic modifications of histones. DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of local chromatin relaxation. We studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts and phosphorylates Tip60. This phosphorylation of Tip60 is lost by depletion of VRK1 in both ATM +/+ and ATM -/- cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses. Dynamic remodeling of chromatin requires acetylation and methylation of histones, frequently affecting the same lysine residue. These alternative epigenetic modifications require the coordination of enzymes, writers and erasers, mediating them such as acetylases and deacetylases. In cells in G0/G1, DNA damage induced by doxorubicin causes an increase in histone H4K16ac, a marker of chromatin relaxation. In this context, we studied the role that VRK1, a chromatin kinase activated by DNA damage, plays in this early step. VRK1 depletion or MG149, a Tip60/KAT5 inhibitor, cause a loss of H4K16ac. DNA damage induces the phosphorylation of Tip60 mediated by VRK1 in the chromatin fraction. VRK1 directly interacts with and phosphorylates Tip60. Furthermore, the phosphorylation of Tip60 induced by doxorubicin is lost by depletion of VRK1 in both ATM +/+ and ATM -/- cells. Kinase-active VRK1, but not kinase-dead VRK1, rescues Tip60 phosphorylation induced by DNA damage independently of ATM. The Tip60 phosphorylation by VRK1 is necessary for the activating acetylation of ATM, and subsequent ATM autophosphorylation, and both are lost by VRK1 depletion. These results support that the VRK1 chromatin kinase is an upstream regulator of the initial acetylation of histones, and an early step in DNA damage responses (DDR).
Grants:	Agencia Estatal de Investigación SAF2016-75744-R Ministerio de Economía y Competitividad RED2018-102801-T Agencia Estatal de Investigación PID2019-105610RB-I0 Ministerio de Educación, Cultura y Deporte FPU-16-01883 Ministerio de Economía y Competitividad BES-2014-0677
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Phosphorylation ; Histone H4 ; Acetylation ; DNA-damage response ; Nucleosomal histone kinase-1
Published in:	Cancers, Vol. 12 (october 2020) , ISSN 2072-6694

DOI: 10.3390/cancers12102986
PMID: 33076429

24 p, 6.9 MB

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