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Guided nuclear exploration increases CTCF target search efficiency

View ORCID ProfileAnders S. Hansen, Assaf Amitai, View ORCID ProfileClaudia Cattoglio, View ORCID ProfileRobert Tjian, View ORCID ProfileXavier Darzacq
doi: https://doi.org/10.1101/495457
Anders S. Hansen
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, USA
2Li Ka Shing Center for Biomedical and Health Sciences
3CIRM Center of Excellence, University of California, Berkeley, Berkeley, USA
4Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, USA
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  • ORCID record for Anders S. Hansen
Assaf Amitai
5Department of Chemical Engineering, MIT, Cambridge 02139, Massachusetts, USA
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Claudia Cattoglio
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, USA
2Li Ka Shing Center for Biomedical and Health Sciences
3CIRM Center of Excellence, University of California, Berkeley, Berkeley, USA
4Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, USA
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Robert Tjian
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, USA
2Li Ka Shing Center for Biomedical and Health Sciences
3CIRM Center of Excellence, University of California, Berkeley, Berkeley, USA
4Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, USA
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Xavier Darzacq
1Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, USA
2Li Ka Shing Center for Biomedical and Health Sciences
3CIRM Center of Excellence, University of California, Berkeley, Berkeley, USA
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Abstract

Mammalian genomes are enormous. For a DNA-binding protein, this means that the number of non-specific, off-target sites vastly exceeds the number of specific, cognate sites. How mammalian DNA-binding proteins overcome this challenge to efficiently locate their target sites is not known. Here through live-cell single-molecule tracking, we show that CCCTC-binding factor, CTCF, is repeatedly trapped in small zones in the nucleus in a manner that is largely dependent on its RNA-binding region (RBR). Integrating theory, we devise a new model, Anisotropic Diffusion through transient Trapping in Zones (ADTZ), to explain this. Functionally, transient RBR-mediated trapping increases the efficiency of CTCF target search by ∼2.5 fold. Since the RBR-domain also mediates CTCF clustering, our results suggest a “guided” mechanism where CTCF clusters concentrate diffusing CTCF proteins near cognate binding sites, thus increasing the local ON-rate. We suggest that local “guiding” may represent a general target search mechanism in mammalian cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 13, 2018.
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Guided nuclear exploration increases CTCF target search efficiency
Anders S. Hansen, Assaf Amitai, Claudia Cattoglio, Robert Tjian, Xavier Darzacq
bioRxiv 495457; doi: https://doi.org/10.1101/495457
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Guided nuclear exploration increases CTCF target search efficiency
Anders S. Hansen, Assaf Amitai, Claudia Cattoglio, Robert Tjian, Xavier Darzacq
bioRxiv 495457; doi: https://doi.org/10.1101/495457

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