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

• Published in: Chemico-biological interactions Vol. 391; p. 110908
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.03.2024
• Subjects: Cancer; Chromatin; DNA damage; Doxorubicin; Nuclear proteins; Phosphoproteomics; VRK1; Nuclear proteins; Chromatin; Phosphoproteomics; DNA damage; VRK1; Doxorubicin; Cancer
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2024.110908

Dynamic chromatin remodeling requires regulatory mechanisms for its adaptation to different nuclear function, which are likely to be mediated by signaling proteins. In this context, VRK1 is a nuclear Ser-Thr kinase that regulates pathways associated with transcription, replication, recombination, and DNA repair. Therefore, VRK1 is a potential regulatory, or coordinator, molecule in these processes. In this work we studied the effect that VRK1 depletion has on the basal nuclear and chromatin phosphoproteome, and their associated pathways. VRK1 depletion caused an alteration in the pattern of the nuclear phosphoproteome, which is mainly associated with nucleoproteins, ribonucleoproteins, RNA splicing and processing. Next, it was determined the changes in proteins associated with DNA damage that was induced by doxorubicin treatment. Doxorubicin alters the nuclear phosphoproteome affecting proteins implicated in DDR, including DSB repair proteins NBN and 53BP1, cellular response to stress and chromatin organization proteins. In VRK1-depleted cells, the effect of doxorubicin on protein phosphorylation was reverted to basal levels. The nuclear phosphoproteome patterns induced by doxorubicin are altered by VRK1 depletion, and is enriched in histone modification proteins and chromatin associated proteins. These results indicate that VRK1 plays a major role in processes requiring chromatin remodeling in its adaptation to different biological contexts. •VRK1 depletion alters the phosphorylation of nuclear and chromatin phosphoproteins.•Doxorubicin alters phosphorylation pattern of chromatin-related proteins.•VRK1 loss impairs the nuclear phospho proteome induced by doxorubicin.