Regulation of checkpoint kinase signalling and tumorigenesis by the NF-κB regulated gene, CLSPN
Jill E Hunter,
Jacqueline A Butterworth,
Adam J Moore,
Huw D Thomas,
Kirsteen J Campbell,
Niall S Kenneth,
Robson T Chiremba,
Andrew M Knight,
Michelle D Garrett,
Neil D Perkins
Posted 28 Jun 2018
bioRxiv DOI: 10.1101/358291
Posted 28 Jun 2018
Inhibition of the tumour promoting activities of NF-κB by cell signalling pathways has been proposed as a natural mechanism to limit the development of cancer. However, there has been a lack of evidence for these effects in vivo. Here we report that RelAT505A mice, where a CHK1 targeted Thr505 phosphosite is mutated to alanine, display earlier onset of MYC driven lymphoma than wild type littermates. We describe a positive feedback loop in which the NF-κB subunits RelA and c-Rel, in a manner dependent upon RelA Thr505 phosphorylation, drive the expression of the ATR checkpoint kinase regulator Claspin in response to DNA replication stress in cancer cells. This in turn is required for maintenance of CHK1 activity. Loss of a single allele of the Clspn gene in mice is sufficient to drive earlier tumorigenesis and low levels of CLSPN mRNA expression are associated with worse survival in some forms of human cancer. We propose that loss of this pathway early in tumorigenesis promotes cancer development through increased genomic instability. However, in malignant cancer cells it can help promote their addiction to the checkpoint kinase signalling required for the maintenance of genomic integrity. Importantly, disruption of this pathway leads to resistance of cells to treatment with CHK1 inhibitors. Claspin expression could therefore act as a biomarker for responsiveness of patients to CHK1 inhibitors and provide a potential pathway for the development of tumour resistance.
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