Claspin functions in cell homeostasis—A link to cancer?

Azenha, Diana; Lopes, María Celeste; Martins, Teresa

doi:10.1016/j.dnarep.2017.09.002

Cited by 27 publications

(32 citation statements)

References 107 publications

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“…CLSPN is involved in the DNA damage checkpoint (Chini & Chen, ) and is required for the activation of CHK1 during a DNA replication checkpoint response (Kumagai & Dunphy, ). It is also involved in DNA replication and repair of DNA damage repair and may function as a tumor suppressor gene (Azenha, Lopes, & Martins, ). Nine somatic truncating mutations in CLSPN have been reported in CRC in cBioPortal including one at position 1139, that is, more distal to our variant.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing in 51 early onset non‐familial CRC cases

Thutkawkorapin

Lindblom

Tham

2019

Molec Gen & Gen Med

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Background Colorectal cancer ( CRC ) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi‐allelic autosomal recessive pathogenic variants. Methods The cohort was whole exome sequenced ( WES ) at 100× coverage. Both a dominant‐ and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young‐onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss‐of‐function) or allele frequency. Results We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS 2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes ( BMPR 1A , BRIP 1 , and SRC ) , three truncating variants in possibly novel cancer genes ( CLSPN , SEC 24B , SSH 2 ) and four candidate missense variants in ACACA , NR 2C2 , INPP 4A, and DIDO 1 . We also identify five possible autosomal recessive candidate genes: ATP 10B , PKHD 1 , UGGT 2 , MYH 13 , TFF 3 . Conclusion Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing in 51 early onset non‐familial CRC cases

Thutkawkorapin

Lindblom

Tham

2019

Molec Gen & Gen Med

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“…Downregulation of claspin, and ATR and Chk1, greatly reduces cell survival and promotes alterations in cell cycle checkpoints and DNA repair systems . These alterations could lead to genomic instability that triggers cancer development . However, it has been reported that overexpression of claspin contributes to tumor proliferation in several human solid tumors, such as colon, lung, bladder, breast, ovarian, and cervical cancers .…”

Section: Introductionmentioning

confidence: 99%

“…12 These alterations could lead to genomic instability that triggers cancer development. [14][15][16] However, it has been reported that overexpression of claspin contributes to tumor proliferation in several human solid tumors, such as colon, lung, bladder, breast, ovarian, and cervical cancers. [16][17][18][19] Previously, we identified upregulation of the CLSPN gene in spheroid body-forming GC cell lines.…”

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confidence: 99%

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

et al. 2020

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Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin‐positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA‐transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand‐1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule.

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“…Claspin is an adaptor protein associated with DNA replication forks that is required for ATR dependent phosphorylation of CHK1 following DNA replication stress and other forms of DNA damage. Claspin can also function as a sensor to monitor the integrity of DNA replication forks through binding to branched DNA structures (Azenha et al, 2017;Chini and Chen, 2004;Errico and Costanzo, 2012;Kumagai and Dunphy, 2003). Claspin inactivation contributes to malignant transformation of cell lines by oncogenic viruses (Hein et al, 2009;Koganti et al, 2014;Spardy et al, 2009) such as human papillomavirus.…”

Section: Loss Of Claspin Expression In Eµ-myc/rela T505a and Eµ-myc/cmentioning

confidence: 99%

“…Proteolytic degradation of Claspin has also been shown to disrupt ATR/CHK1 signalling and promote EBV transformation of primary Bcells (Koganti et al, 2014). Consequently, it has been suggested that Claspin inactivation could be an essential event during carcinogenesis (Azenha et al, 2017), although evidence for this at the genetic level has not been established. Moreover, Rad17, a vital component of the replication stress response has previously been reported as a putative tumour suppressor in murine lymphoma (Bric et al, 2009), indicating that this pathway is essential for the maintenance of genome integrity.…”

Section: Loss Of Claspin Expression In Eµ-myc/rela T505a and Eµ-myc/cmentioning

confidence: 99%

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

Hunter¹,

Butterworth²,

Sellier³

et al. 2018

Preprint

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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.

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Claspin functions in cell homeostasis—A link to cancer?

Cited by 27 publications

References 107 publications

Exome sequencing in 51 early onset non‐familial CRC cases

Exome sequencing in 51 early onset non‐familial CRC cases

Claspin overexpression is associated with high‐grade histology and poor prognosis in renal cell carcinoma

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

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