The VRK1 chromatin kinase regulates the acetyltransferase activity of Tip60/KAT5 by sequential phosphorylations in response to DNA damage

García-González, Raúl; Monte-Serrano, Eva; Morejón‐García, Patricia; Navarro-Carrasco, Elena; Lazo, Pedro A.

doi:10.1016/j.bbagrm.2022.194887

Cited by 9 publications

(15 citation statements)

References 83 publications

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“…The role of VRK1 in the modulation of epigenetic histone modifications is likely to be due to its interaction with members of these protein families. It is known that VRK1 interacts with the Tip60/KAT5 and regulates its translocation from nucleoplasm to chromatin and its activity [ 30 , 31 ]. Therefore, it is likely that VRK1 might also form complexes with other members of these epigenetic enzyme families.…”

Section: Resultsmentioning

confidence: 99%

“…Its combination with a VRK1 inhibitor targeting different pathways, such as proliferation signals, as well as DNA responses such as those mediated by p53, or those associated with different and early steps in DDR such as the formation of γH2AX foci in the response to doxorubicin or ionizing radiation [ 51 , 66 ] regulated by VRK1 or olaparib, a PARP inhibitor [ 67 ]. Furthermore, inhibition of histone H4 acetylation impairs DDR, which by itself may not be enough [ 68 ], but can cooperate with VRK1 inhibition in the elimination of tumor cells [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Previously, it has been shown that VRK1 specifically phosphorylates Tip60/KAT5 facilitating its translocation to chromatin and activating the acetylation of H4K16 in the response to DNA damage [ 30 , 31 ]. The reversal of this acetylation requires histone deacetylases (HDACs).…”

Section: Discussionmentioning

confidence: 99%

“…H4K16 acetylation controls chromatin organization and protein interactions [ 29 ]. The phosphorylation of histone H3 in Thr3 is required for phosphorylating and recruiting KAT5/Tip60 to chromatin [ 30 , 31 ]. VRK1 phosphorylates and activates Tip60/KAT5 and regulates the acetylation of H4K16 [ 30 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

“…The phosphorylation of histone H3 in Thr3 is required for phosphorylating and recruiting KAT5/Tip60 to chromatin [ 30 , 31 ]. VRK1 phosphorylates and activates Tip60/KAT5 and regulates the acetylation of H4K16 [ 30 , 31 ]. In DNA damage responses (DDR), VRK1 also phosphorylates H2AX in Ser139 (γH2AX) [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

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The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

Monte-Serrano,

Morejón-García,

Campillo-Marcos

et al. 2023

Epigenetics & Chromatin

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Background Dynamic chromatin remodeling is associated with changes in the epigenetic pattern of histone acetylations and methylations required for processes based on dynamic chromatin remodeling and implicated in different nuclear functions. These histone epigenetic modifications need to be coordinated, a role that may be mediated by chromatin kinases such as VRK1, which phosphorylates histones H3 and H2A. Methods The effect of VRK1 depletion and VRK1 inhibitor, VRK-IN-1, on the acetylation and methylation of histone H3 in K4, K9 and K27 was determined under different conditions, arrested or proliferating cells, in A549 lung adenocarcinoma and U2OS osteosarcoma cells. Results Chromatin organization is determined by the phosphorylation pattern of histones mediated by different types of enzymes. We have studied how the VRK1 chromatin kinase can alter the epigenetic posttranslational modifications of histones by using siRNA, a specific inhibitor of this kinase (VRK-IN-1), and of histone acetyl and methyl transferases, as well as histone deacetylase and demethylase. Loss of VRK1 implicated a switch in the state of H3K9 posttranslational modifications. VRK1 depletion/inhibition causes a loss of H3K9 acetylation and facilitates its methylation. This effect is similar to that of the KAT inhibitor C646, and to KDM inhibitors as iadademstat (ORY-1001) or JMJD2 inhibitor. Alternatively, HDAC inhibitors (selisistat, panobinostat, vorinostat) and KMT inhibitors (tazemetostat, chaetocin) have the opposite effect of VRK1 depletion or inhibition, and cause increase of H3K9ac and a decrease of H3K9me3. VRK1 stably interacts with members of these four enzyme families. However, VRK1 can only play a role on these epigenetic modifications by indirect mechanisms in which these epigenetic enzymes are likely targets to be regulated and coordinated by VRK1. Conclusions The chromatin kinase VRK1 regulates the epigenetic patterns of histone H3 acetylation and methylation in lysines 4, 9 and 27. VRK1 is a master regulator of chromatin organization associated with its specific functions, such as transcription or DNA repair.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

Monte-Serrano,

Morejón-García,

Campillo-Marcos

et al. 2023

Epigenetics & Chromatin

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Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy

Campos-Díaz,

Morejón-García,

Monte-Serrano

et al. 2024

J Mol Med

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Rare recessive variants in the human VRK1 gene are associated with several motor neuron diseases (MND), such as amyotrophic lateral sclerosis, spinal muscular atrophy, or distal hereditary motor neuropathies (dHMN). A case with dHMN carrying two novel VRK1 gene variants, expressing Leu200Pro (L200P) and Arg387His (R387H) variant proteins, identified that these protein variants are functionally different. The Leu200Pro variant shares with several variants in the catalytic domain the loss of the kinase activity on different substrates, such as histones, p53, or coilin. However, the distal Arg387His variant and the distal Trp375* (W375X) chinese variant, both located at the end of the low complexity C-terminal region and proximal to the termination codon, retain their catalytic activity on some substrates, and mechanistically their functional impairment is different. The L200P variant, as well as most VRK1 pathogenic variants, impairs the phosphorylation of BAF and histone H4K16 acetylation, which are required for DNA attachment to the nuclear envelope and chromatin accessibility to DNA repair mechanisms, respectively. The R387H variant impairs phosphorylation of H2AX, an early step in different types of DNA damage responses. The functional variability of VRK1 protein variants and their different combinations are a likely contributor to the clinical phenotypic heterogeneity of motor neuron and neurological diseases associated with rare VRK1 pathogenic variants. Key messages VRK1 variants implicated in motor neuron diseases are functionally different. The L200P variant is kinase inactive, and the R387H variant is partially active. VRK1 variants alter H4K16 acetylation and loss of coilin and BAF phosphorylation. VRK1 variants alter Cajal bodies and DNA damage responses. VRK1 variant combination determines the neurological phenotype heterogeneity.

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Loss of VRK1 alters the nuclear phosphoproteome in the DNA damage response to doxorubicin

Navarro-Carrasco,

Campos-Díaz,

Monte-Serrano

et al. 2024

Chemico-Biological Interactions

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The VRK1 chromatin kinase regulates the acetyltransferase activity of Tip60/KAT5 by sequential phosphorylations in response to DNA damage

Cited by 9 publications

References 83 publications

The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

The pattern of histone H3 epigenetic posttranslational modifications is regulated by the VRK1 chromatin kinase

Pathogenic effects of Leu200Pro and Arg387His VRK1 protein variants on phosphorylation targets and H4K16 acetylation in distal hereditary motor neuropathy

Loss of VRK1 alters the nuclear phosphoproteome in the DNA damage response to doxorubicin

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