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

Navarro-Carrasco, Elena; Campos-Díaz, Aurora; Monte-Serrano, Eva; Rolfs, Frank; de Goeij-de Haas, Richard; Pham, Thang V.; Piersma, Sander R.; Jiménez, Connie R.; Lazo, Pedro A.

doi:10.1016/j.cbi.2024.110908

Cited by 3 publications

(2 citation statements)

References 57 publications

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“…This is consistent with the initial manifestation of the neurological syndromes in distal parts of the body in patients with pathogenic VRK1 variants. Chromatin alterations can also be a consequence of modifications in the pattern of its epigenetic modifications [ 32 ]. The alteration of chromatin relaxation as a consequence of pathogenic VRK1 variants, which impairs histone H4K16 acetylation, can alter not only DNA damage responses, but also the differentiation of neurons during development.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…VRK1 directly interacts and phosphorylates Tip60 promoting its translocation to chromatin and its transacetylase activity in the DNA damage response [ 27 , 30 ]. VRK1 depletion also alters several nuclear phosphoproteome pathways in the response to DNA damage [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

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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Nuclear functions regulated by the VRK1 kinase

Lazo

2024

Nucleus

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VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells

Navarro-Carrasco,

Monte-Serrano,

Campos-Díaz

et al. 2024

IJMS

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The chromatin organization and its dynamic remodeling determine its accessibility and sensitivity to DNA damage oxidative stress, the main source of endogenous DNA damage. We studied the role of the VRK1 chromatin kinase in the response to oxidative stress. which alters the nuclear pattern of histone epigenetic modifications and phosphoproteome pathways. The early effect of oxidative stress on chromatin was studied by determining the levels of 8-oxoG lesions and the alteration of the epigenetic modification of histones. Oxidative stress caused an accumulation of 8-oxoG DNA lesions that were increased by VRK1 depletion, causing a significant accumulation of DNA strand breaks detected by labeling free 3′-DNA ends. In addition, oxidative stress altered the pattern of chromatin epigenetic marks and the nuclear phosphoproteome pathways that were impaired by VRK1 depletion. Oxidative stress induced the acetylation of H4K16ac and H3K9 and the loss of H3K4me3. The depletion of VRK1 altered all these modifications induced by oxidative stress and resulted in losses of H4K16ac and H3K9ac and increases in the H3K9me3 and H3K4me3 levels. All these changes were induced by the oxidative stress in the epigenetic pattern of histones and impaired by VRK1 depletion, indicating that VRK1 plays a major role in the functional reorganization of chromatin in the response to oxidative stress. The analysis of the nuclear phosphoproteome in response to oxidative stress detected an enrichment of the phosphorylated proteins associated with the chromosome organization and chromatin remodeling pathways, which were significantly decreased by VRK1 depletion. VRK1 depletion alters the histone epigenetic pattern and nuclear phosphoproteome pathways in response to oxidative stress. The enzymes performing post-translational epigenetic modifications are potential targets in synthetic lethality strategies for cancer therapies.

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

Cited by 3 publications

References 57 publications

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

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

Nuclear functions regulated by the VRK1 kinase

VRK1 Regulates Sensitivity to Oxidative Stress by Altering Histone Epigenetic Modifications and the Nuclear Phosphoproteome in Tumor Cells

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