Ian Hickson – University of Copenhagen

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Ian Hickson

Our research is focused on understanding how chromosomal instability impacts on human disease. We study genes in human cells that, when mutated, lead to defective genome maintenance and high rates of cancer, neurodegeneration or infertility.

In recent years we have focused on common fragile sites as a model for understanding how ‘difficult-to-replicate’ regions of the human genome affect propagation of the genome through successive cell divisions. As part of these studies, we identified ultra-fine anaphase bridges (UFBs) which are DNA thread-like structures connecting the separating sister chromatids in the anaphase of mitosis. These UFBs exist in every human cell division but are normally ‘invisible’ due to their lack of staining with DNA dyes. They are coated with specific proteins, including the SNF2 family protein, PICH and the BLM helicase (which when mutated causes Bloom’s syndrome – a cancer predisposition disorder), that allows detection using specific antibodies.

We combine protein biochemistry with molecular/cell biology and high resolution imaging of human cells. Latterly, we have also been developing tools to exploit new developments in microfluidics and single molecule biophysical techniques to reconstitute in vitro defined steps in DNA metabolism.

Figure: An example of a fragile site-associated ultra-fine anaphase DNA bridge marked by BLM (red) on the bridge and FANCD2 foci (green) on the termini. DNA is in blue.

 

 

 

 

 

 

 

 

 

For further reading on the Hickson Lab, see the following:

  1. Chan, K-L., Palmai-Pallag, T., Ying, S. and Hickson, I.D. (2009) Replication stress induces sister-chromatid bridging at fragile site loci in mitosis.  Nature Cell Biology 11, 753-760.
  2. Bhowmick R, Minocherhomji S, Hickson ID. RAD52 Facilitates Mitotic DNA Synthesis Following Replication Stress. Mol Cell. 2016 Dec 15;64(6):1117-1126.
  3. Biebricher, A., Hirano, S., Enzlin, J.H., Wiechens, N., Streicher, W.W., Wang, L.H.C., Nigg, E.A., Owen-Hughes, T., Liu, Y., Peterman, E., Wuite, G.J.L. and Hickson, I.D. (2013) PICH: a DNA translocase specially adapted for processing anaphase bridge DNA. Molecular Cell 51, 691-701.
  4. Ying, S., Minocherhomji, S., Chan, K.L., Palmai-Pallag, T., Chu, W.K., Wass, T., Mankouri, H.W., Liu, Y. and Hickson, I.D. (2013) MUS81 promotes common fragile site expression. Nature Cell Biol. 15, 1001-1006.
  5. Mankouri, H.W., Huttner, D. and Hickson, I.D. (2013) How unfinished business from S-phase affects mitosis and beyond. EMBO J. 32, 2661-2671.
  6. Minocherhomji, S. and Hickson, I.D. (2014) Structure-specific endonucleases: guardians of fragile site stability. Trends in Cell Biology 24, 321-327.
  7. Nielsen CF, Huttner D, Bizard AH, Hirano S, Li TN, Palmai-Pallag T, Bjerregaard VA, Liu Y, Nigg EA, Wang LH, Hickson ID. PICH promotes sister chromatid disjunction and co-operates with topoisomerase II in mitosis. Nat Commun. 2015 Dec 8; 6:8962.
  8. Minocherhomji, S., Ying, S., Bjerregaard, V.A., Bursomanno, S., Aleliunaite, A., Wu, W., Mankouri, H.W., Shen, H., Liu, Y. and Hickson, I.D. (2015) Replication stress activates DNA repair synthesis in mitosis. Nature 528, 286-290.