Regulation of checkpoint kinase signalling and tumorigenesis by the NF-κB regulated gene, CLSPN

Abstract

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 RelA T505A 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.

Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response

“…Therefore, the loss of CLSPN that is associated with SLF2 deficiency is in agreement with impaired CHK1 activation in SLF2 KO cells. Of note, a recent study provided genetic evidence that CLSPN‐deficient mice developed spontaneous B‐cell lymphomas (preprint: Hunter et al , 2018 ). Together, these findings indicate a mechanism by which CLSPN loss subsequent to SLF2 deficiency may explain the tumor suppressor function of SLF2, while SLF2 also acts as a regulator of several factors involved in cell cycle progression and DNA repair.…”

“…Whereas a subtle reduction of CHK1 activity is beneficial for the accumulation of tumor‐promoting mutations and drives tumorigenesis, full loss of CHK1 activity is toxic even for tumor cells due to the excessive and irrepressible level of DNA damage (Bric et al , 2009 ). This concept is empowered by a recent report revealing that deficiency for CLSPN, which act as fine‐tuner of CHK1 activity, resulted in spontaneous B‐cell lymphomagenesis (preprint: Hunter et al , 2018 ). Other than CHK1, the complete loss of the ATM/CHK2 axis is considered tumor‐promoting and the ATM locus is frequently affected by deletions of the long arm of chromosome 11 (Choi et al , 2016 ).…”

New insights into the genetic mechanisms of body size evolution in Carnivora

“…Additionally, 16 BSAGs were found to be related with "DNA repair" and it was well known that de cits in DNA repair capacity might lead to genetic instability and carcinogenesis [49]. Recent study revealed that loss of a single allele of the CLSPN (claspin) gene in mice was su cient to drive earlier tumorigenesis [50]. And HELQ (Helicase, POLQ like) played a critical role for replication-coupled DNA repair, germ cell maintenance and tumor suppression in mammals [51].…”