Abstract
Claspin is a multifunctional protein that participates in physiological processes essential for cell homeostasis that are often defective in cancer, namely due to genetic changes. It is conceivable that Claspin gene (CLSPN) alterations may contribute to cancer development. Therefore, CLSPN germline alterations were characterized in sporadic and familial breast cancer and glioma samples, as well as in six cancer cell lines. Their association to cancer susceptibility and functional impact were investigated. Eight variants were identified (c.-68C>T, c.17G>A, c.1574A>G, c.2230T>C, c.2028+16G>A, c.3595-3597del, and c.3839C>T). CLSPN c.1574A>G (p.Asn525Ser) was significantly associated with breast cancer and was shown to cause partial exon skipping and decreased Claspin expression and Chk1 activation in a minigene splicing assay and in signalling experiments, respectively. CLSPN c.2028+16G>A was significantly associated with familial breast cancer and glioma, whereas c.2230T>C (p.Ser744Pro), was exclusively detected in breast cancer and glioma patients, but not in healthy controls. The remaining variants lacked a significant association with cancer. Nevertheless, the c.-68C>T promoter variant increased transcriptional activity in a luciferase assay. In conclusion, some of the CLSPN variants identified in the present study appear to modulate Claspin’s function by altering CLSPN transcription and RNA processing, as well as Chk1 activation.
Highlights
Cancer cells derive from the transformation of healthy cells after progressive and cumulative acquisition of genetic and epigenetic alterations that affect essential cellular functions [1,2]
We began by characterizing the spectrum of Claspin gene (CLSPN) germline alterations occurring in familial breast cancer (n = 147), sporadic breast cancer (n = 66) and in glioma (n = 53) patients
We found that the c.1574A>G (p.Asn525Ser) variant was associated with sporadic and familial breast cancer, whereas c.2028+16G>A was linked to glioma
Summary
Cancer cells derive from the transformation of healthy cells after progressive and cumulative acquisition of genetic and epigenetic alterations that affect essential cellular functions [1,2]. Claspin integrates the functions of a group of crucial proteins with the maintenance of genome stability [4], by being an important player in key cellular events such as checkpoint activation after. Checkpoint activation after DNA damage provides cells time to repair the damage before cell cycle progression. If this is not possible, checkpoints are deactivated and the cells induced to die, namely by apoptosis.
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