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Abstract
Multiple functions have been reported for the transcription factor and candidate tumour suppressor, CTCF. Among others, they include regulation of cell growth, differentiation and apoptosis, enhancer-blocking activity and control of imprinted genes. CTCF is usually localized in the nucleus and its subcellular distribution during the cell cycle is dynamic; CTCF was found associated with mitotic chromosomes and the midbody, suggesting different roles for CTCF at different stages of the cell cycle. Here we report the nucleolar localization of CTCF in several experimental model systems. Translocation of CTCF from nucleoplasm to the nucleolus was observed after differentiation of K562 myeloid cells and induction of apoptosis in MCF7 breast cancer cells. CTCF was also found in the nucleoli in terminally differentiated rat trigeminal ganglion neurons. Thus our data show that nucleolar localization of CTCF is associated with growth arrest. Interestingly, the 180 kDa poly(ADP-ribosyl)ated isoform of CTCF was predominantly found in the nucleoli fractions. By transfecting different CTCF deletion constructs into cell lines of different origin we demonstrate that the central zinc-finger domain of CTCF is the region responsible for nucleolar targeting. Analysis of subnucleolar localization of CTCF revealed that it is distributed homogeneously in both dense fibrillar and granular components of the nucleolus, but is not associated with fibrillar centres. RNA polymerase I transcription and protein synthesis were required to sustain nucleolar localization of CTCF. Notably, the labelling of active transcription sites by in situ run-on assays demonstrated that CTCF inhibits nucleolar transcription through a poly(ADP-ribosyl)ation-dependent mechanism.
Highlights
A growing body of evidence reveals the complexity of function of the transcriptional factor CTCF (Klenova et al, 2002; Ohlsson et al, 2001)
CTCF is targeted to the nucleolus upon different stimuli We first explored CTCF localization upon induced differentiation by taking advantage of the ability of K562 leukaemia cells to undergo pluripotent myeloid differentiation (Munoz-Alonso et al, 2005)
K562 were differentiated into an erythroid lineage with 1--Darabinofuranosylcytosine (Ara-C) or into a megakaryocytic lineage with staurosporine (STA), and undifferentiated K562 were used as control
Summary
A growing body of evidence reveals the complexity of function of the transcriptional factor CTCF (Klenova et al, 2002; Ohlsson et al, 2001). CTCF is the only protein identified so far that mediates enhancer-blocking activity of vertebrate insulators (Bell et al, 1999). CTCF employs different combinations of individual zinc fingers for its binding within promoters, silencers and insulators (reviewed by Dunn and Davie, 2003; Klenova et al, 2002; Ohlsson et al, 2001). Another complexity to understand CTCF functions is the fact that CTCF protein undergoes posttranslational modifications. It can be phosphorylated by the protein kinase CK2 (El-Kady and Klenova, 2005; Klenova et al, 2001), as well as poly(ADP-ribosyl)ated, and this latter modification regulates its activity as a chromatin insulator (Klenova and Ohlsson, 2005; Yu et al, 2004)
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