VRK1 chromatin kinase phosphorylates H2AX and is required for foci formation induced by DNA damage.
All types of DNA damage cause a local alteration and relaxation of chromatin structure. Sensing and reacting to this initial chromatin alteration is a necessary trigger for any type of DNA damage response (DDR). In this context, chromatin kinases are likely candidates to participate in detection and reaction to a locally altered chromatin as a consequence of DNA damage and, thus, initiate the appropriate cellular response. In this work, we demonstrate that VRK1 is a nucleosomal chromatin kinase and that its depletion causes loss of histones H3 and H4 acetylation, which are required for chromatin relaxation, both in basal conditions and after DNA damage, independently of ATM. Moreover, VRK1 directly and stably interacts with histones H2AX and H3 in basal conditions. In response to DNA damage induced by ionizing radiation, histone H2AX is phosphorylated in Ser139 by VRK1. The phosphorylation of H2AX and the formation of γH2AX foci induced by ionizing radiation (IR), are prevented by VRK1 depletion and are rescued by kinase-active, but not kinase-dead, VRK1. In conclusion, we found that VRK1 is a novel chromatin component that reacts to its alterations and participates very early in DDR, functioning by itself or in cooperation with ATM.
a Experimental Therapeutics and Translational Oncology Program; Instituto de Biología Molecular y Celular del Cáncer; Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca; Campus Miguel de Unamuno ; Salamanca , Spain.
Marcella
M
Salzano
Marta
M
Sanz-García
Diana M
DM
Monsalve
David S
DS
Moura
Pedro A
PA
Lazo
D000107:Acetylation / Q000187:drug effects / Q000528:radiation effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011753:Pyrones / Q000494:pharmacology; D011839:Radiation, Ionizing; D012694:Serine / Q000378:metabolism
D002843:Chromatin; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011753:Pyrones; D012694:Serine; C495818:2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one; C468783:H2AX protein, human; C109890:VRK1 protein, human
DDR, DNA-damage response; DNA-damage response; H2AX; IR radiation; VRK1; VRK1 Vaccinia-related kinase 1; chromatin; kinase; nucleosome; radiation