Abstract
BackgroundCGGBP1 is a CGG-triplet repeat binding protein, which affects transcription from CGG-triplet-rich promoters such as the FMR1 gene and the ribosomal RNA gene clusters. Earlier, we reported some previously unknown functions of CGGBP1 in gene expression during heat shock stress response. Recently we had found CGGBP1 to be a cell cycle regulatory midbody protein required for normal cytokinetic abscission in normal human fibroblasts, which have all the cell cycle regulatory mechanisms intact.ResultsIn this study we explored the role of CGGBP1 in the cell cycle in various cancer cell lines. CGGBP1 depletion by RNA interference in tumor-derived cells caused an increase in the cell population at G0/G1 phase and reduced the number of cells in the S phase. CGGBP1 depletion also increased the expression of cell cycle regulatory genes CDKN1A and GAS1, associated with reductions in histone H3 lysine 9 trimethylation in their promoters. By combining RNA interference and genetic mutations, we found that the role of CGGBP1 in cell cycle involves multiple mechanisms, as single deficiencies of CDKN1A, GAS1 as well as TP53, INK4A or ARF failed to rescue the G0/G1 arrest caused by CGGBP1 depletion.ConclusionsOur results show that CGGBP1 expression is important for cell cycle progression through multiple parallel mechanisms including the regulation of CDKN1A and GAS1 levels.
Highlights
CGGBP1 is a CGG-triplet repeat binding protein, which affects transcription from CGG-triplet-rich promoters such as the FMR1 gene and the ribosomal RNA gene clusters
CGGBP1 deficiency increases the expression of some key cell cycle regulatory genes To identify the mechanisms through which CGGBP1 depletion might cause the cell cycle arrest at G0/G1 phase, we focused on the function of CGGBP1 as a transcription-regulatory protein
While we found increases in the transcript levels of TP53, CDKN1A, GAS1 and ARF genes after CGGBP1 depletion, we addressed the mechanism of expression regulation only for CDKN1A and GAS1 genes as only for these genes the changes in transcript levels were correlated with a change in protein levels
Summary
CGGBP1 is a CGG-triplet repeat binding protein, which affects transcription from CGG-triplet-rich promoters such as the FMR1 gene and the ribosomal RNA gene clusters. We reported some previously unknown functions of CGGBP1 in gene expression during heat shock stress response. We had found CGGBP1 to be a cell cycle regulatory midbody protein required for normal cytokinetic abscission in normal human fibroblasts, which have all the cell cycle regulatory mechanisms intact. CGGBP1 was identified as a CGG triplet repeat binding protein in vitro [1]. We found that CGGBP1 participates in heat shock stress response by regulating HSF1 expression through heat-sensitive interactions with NFIX and HMGN1 [2,3]. In normal human fibroblasts, which are expected to have all the checkpoints and DNA repair capabilities intact, we recently reported functions of CGGBP1 in cell cycle regulation at the abscission and consequential prevention of tetraploidy [4]. In cancer cells which often have various abnormalities in the cell cycle regulatory mechanisms, function of CGGBP1 is unknown and is of obvious interest since loss of cell cycle regulation is an event central to tumorigenesis.
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