Abstract
In response to genotoxic stress, multiple kinase signaling cascades are activated, many of them directed towards the tumor suppressor p53, which coordinates the DNA damage response (DDR). Defects in DDR pathways lead to an accumulation of mutations that can promote tumorigenesis. Emerging evidence implicates multiple members of the NimA-related kinase (NEK) family (NEK1, NEK10, and NEK11) in the DDR. Here, we describe a function for NEK10 in the regulation of p53 transcriptional activity through tyrosine phosphorylation. NEK10 loss increases cellular proliferation by modulating the p53-dependent transcriptional output. NEK10 directly phosphorylates p53 on Y327, revealing NEK10's unexpected substrate specificity. A p53 mutant at this site (Y327F) acts as a hypomorph, causing an attenuated p53-mediated transcriptional response. Consistently, NEK10-deficient cells display heightened sensitivity to DNA-damaging agents. Further, a combinatorial score of NEK10 and TP53-target gene expression is an independent predictor of a favorable outcome in breast cancers.
Highlights
Eukaryotic cells respond to various forms of DNA damage through distinct DNA damage response (DDR) pathways
The targeted exon contains the “DFG” motif which is required for NEK10 protein kinase activity (Figure S1)
Phenotypic characterization of NEK10Δ/Δ cells, revealed an increase in proliferation and colony-forming ability compared to both parental A549 cells and to NEK10+/+ single cell clones (Figure 1a-c), suggesting a growth-suppressive function for NEK10
Summary
Eukaryotic cells respond to various forms of DNA damage through distinct DNA damage response (DDR) pathways. DDR networks are subject to complex regulation integrating multiple input signals to titer the cellular response to DNA damage. TP53 transcriptional targets govern a wide range of cellular processes, including cell cycle control, apoptosis, senescence, DNA repair, metabolism, immune response and migration [1,2,3,4]. Following DNA damage, ATM/ATR phosphorylates p53 on S15, disrupting its interaction with MDM2, leading to an accumulation of p53 protein and increased transcription of multiple genes associated with the DDR [14,15,16,17,18]. Work in knockout cell lines lacking NEK10 demonstrates its involvement in the control of cellular growth, DNA replication and sensitivity to genotoxic stress. Genomic analyses of breast cancer patient data reveals NEK10 as a candidate prognostic indicator in WT TP53 tumours
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