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Languages: English
Types: Doctoral thesis
Subjects: QR, QH301

Classified by OpenAIRE into

mesheuropmc: hemic and lymphatic diseases, sense organs
Epstein-Barr virus (EBV) immortalises resting B-lymphocyctes and is associated with a\ud diverse range of cancers and establishes a persistent, latent infection in >90% of the\ud world-wide population. Epstein-Barr virus nuclear antigen (EBNA) 3C is one of only\ud six EBV latent proteins that are crucial for B-cell transformation. EBNA3C is known to\ud disrupt cell-cycle control and to progress phase transition at G1/S and G2/M under\ud conditions where cells should growth arrest, but the mechanism by which EBNA3C\ud does this has not been fully determined. The cell-cycle regulator response gene to\ud complement (RGC) 32 was found to be upregulated in EBNA3C-expressing cells in\ud microarray experiments carried out previously. RGC-32 is involved in cell-cycle\ud activation and also plays a role in G1/S and G2/M transition. I have shown that both\ud EBNA3C-expressing cell-lines with upregulated RGC-32 and cell-lines overexpressing\ud RGC-32 alone displayed disrupted G2/M checkpoint control indicating that EBNA3C\ud may overcome cell-cycle control by upregulation of RGC-32. I also confirmed that\ud RGC-32 increases the in vitro kinase activity of CDK1, the key mitotic kinase essential\ud for G2/M transition. Surprisingly, my data showed that EBNA3C only activated RGC-\ud 32 transcription in reporter assays at a very low-level, but stabilised the RGC-32\ud mRNA. Further studies investigating the differential expression of RGC-32 in EBVpositive\ud and negative cells demonstrated that RGC-32 is upregulated in LCLs and\ud tumour (Burkitt’s lymphoma) cell-lines expressing the full panel of latent genes, but\ud intriguingly highly expressed in Burkitt’s lymphoma cell-lines expressing only EBNA\ud 1. I found that this expression pattern correlated with expression of the RUNX1\ud transcription factor. Reporter assays revealed that RUNX1 was able to activate the\ud RGC-32 promoter. Together, this data indicates a new mechanism by which EBNA 3C\ud can disrupt the G2/M checkpoint and highlights a link between RUNX1 and RGC-32\ud expression in B-cells.

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