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Cytoskeletal regulation of a transcription factor by DNA mimicry

Farah Haque, Christian Freniere, Qiong Ye, Nandini Mani, Elizabeth M. Wilson-Kubalek, Pei-I Ku, Ronald A. Milligan, Radhika Subramanian
doi: https://doi.org/10.1101/2021.09.30.462597
Farah Haque
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Christian Freniere
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Qiong Ye
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Nandini Mani
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Elizabeth M. Wilson-Kubalek
3Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
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Pei-I Ku
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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Ronald A. Milligan
3Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA 92037, USA
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Radhika Subramanian
1Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA
2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: radhika@molbio.mgh.harvard.edu
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Abstract

A long-established strategy for transcription regulation is the tethering of transcription factors to cellular membranes. In contrast, the principal effectors of Hedgehog signaling, the Gli transcription factors, are regulated by microtubules in the primary cilium and the cytoplasm. How Gli is tethered to microtubules remains unclear. We uncover DNA mimicry by the ciliary kinesin Kif7 as a mechanism for the recruitment of Gli to microtubules, revealing a new mode of tethering a DNA-binding protein to the cytoskeleton. Gli increases the Kif7-microtubule affinity and consequently modulates the localization of both proteins to microtubules and the cilium tip. Thus, the kinesin-microtubule system is not a passive Gli tether but a regulatable platform tuned by the kinesin-transcription factor interaction. We re-tooled the unique DNA-mimicry-based Gli-Kif7 interaction for inhibiting the nuclear and cilium localization of Gli. This strategy can be potentially exploited for downregulating erroneously activated Gli in human cancers.

Competing Interest Statement

The authors have declared no competing interest.

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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 October 01, 2021.
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Cytoskeletal regulation of a transcription factor by DNA mimicry
Farah Haque, Christian Freniere, Qiong Ye, Nandini Mani, Elizabeth M. Wilson-Kubalek, Pei-I Ku, Ronald A. Milligan, Radhika Subramanian
bioRxiv 2021.09.30.462597; doi: https://doi.org/10.1101/2021.09.30.462597
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Cytoskeletal regulation of a transcription factor by DNA mimicry
Farah Haque, Christian Freniere, Qiong Ye, Nandini Mani, Elizabeth M. Wilson-Kubalek, Pei-I Ku, Ronald A. Milligan, Radhika Subramanian
bioRxiv 2021.09.30.462597; doi: https://doi.org/10.1101/2021.09.30.462597

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