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Published on: June 6, 2017
Loss of CCDC6 affects cell cycle through impaired intra-S-phase checkpoint control
Angeliki Thanasopoulou1, Dimitrios J Stravopodis, Konstantinos S Dimas
1Department of Genetics & Gene Therapy, Biomedical Research Foundation of Academy of Athens, Athens, Greece.
Abstract:
In most cancers harboring Ccdc6 gene rearrangements, like papillary thyroid tumors or myeloproliferative disorders, the product of the normal allele is supposed to be functionally impaired or absent. To address the consequence of the loss of CCDC6 expression, we applied lentiviral shRNA in several cell lines. Loss of CCDC6 resulted in increased cell death with clear shortening of the S phase transition of the cell cycle. Upon exposure to etoposide, the cells lacking CCDC6 did not achieve S-phase accumulation. In the absence of CCDC6 and in the presence of genotoxic stress, like etoposide treatment or UV irradiation, increased accumulation of DNA damage was observed, as indicated by a significant increase of pH2Ax Ser139. 14-3-3σ, a major cell cycle regulator, was down-regulated in CCDC6 lacking cells, regardless of genotoxic stress. Interestingly, in the absence of CCDC6, the well-known genotoxic stress-induced cytoplasmic sequestration of the S-phase checkpoint CDC25C phosphatase did not occur. These observations suggest that CCDC6 plays a key role in cell cycle control, maintenance of genomic stability and cell survival and provide a rational of how disruption of CCDC6 normal function contributes to malignancy.
Insights
Loss of CCDC6 expression leads to increased cell death and DNA damage, impairing cell cycle control. This suggests CCDC6 is crucial for genomic stability and survival, with its disruption contributing to cancer development.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- CCDC6 gene rearrangements are common in cancers like papillary thyroid tumors.
- The functional loss of CCDC6 is implicated in the development of various malignancies.
- Understanding CCDC6's role is crucial for comprehending cancer pathogenesis.
Purpose of the Study:
- To investigate the functional consequences of CCDC6 loss in cell lines.
- To elucidate CCDC6's role in cell cycle regulation and DNA damage response.
- To explore the link between CCDC6 disruption and cancer development.
Main Methods:
- Utilized lentiviral shRNA to deplete CCDC6 expression in multiple cell lines.
- Assessed cell death, cell cycle progression (S phase), and DNA damage markers (pH2Ax Ser139).
- Investigated the expression of cell cycle regulators (14-3-3σ, CDC25C) under genotoxic stress.
Main Results:
- Loss of CCDC6 resulted in increased cell death and shortened S phase.
- Cells lacking CCDC6 showed impaired S-phase accumulation upon etoposide treatment.
- Absence of CCDC6 led to increased DNA damage accumulation and altered CDC25C localization under genotoxic stress.
- Down-regulation of 14-3-3σ was observed in CCDC6-deficient cells.
Conclusions:
- CCDC6 is essential for cell cycle control, genomic stability, and cell survival.
- Disruption of CCDC6 function contributes to malignancy by compromising DNA damage response pathways.
- Findings provide a rationale for CCDC6's role in cancer pathogenesis.
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