https://www.biorxiv.org/content/early/2018/08/21/397448

Despite all the work so for on cell cycle control, we  don't know too much how cyclins, the specificity subunit of cyclin-dependent kinases, find their targets. Surprisingly, this is also true for cyclin D, which launches the human cell cycle, at least in part by phosphorylating the retinoblastoma protein, Rb. We should know how cyclin D recognizes Rb, and now we do... it might actually be important for human health. The cyclin D-Cdk4,6-Rb pathway is just now becoming an important cancer therapeutic pathway with a new series of drugs in clinical trials targeting the ATP binding pocket of Cdk4,6. That these Cdk4,6 inhibitors have significant off-target activites raises the possibility that a new class of drugs targeting cyclin substrate recognition based on our helix docking mechanism could improve cancer therapy (seriously).

On another note, there is something interesting about the cyclin D recognition mechanism. Other cyclins recognize short linear motifs in unstructured regions of the target proteins, while we observe a cyclin recognizing a structural element (an alpha-helix that resides within a previously reported unstructured region) in the C-terminus of Rb. This expands our understanding of structural elements responsible for determining cyclin-dependent kinase targets to drive the many facets of cell division.

Finally, much remains to be done, for example, we still don't know all the mechanisms cyclins E or A use to recognize Rb too... and we should understand that since these are interactions at the very core of the eukaryotic cell cycle.

Posted
AuthorJan Skotheim

Also, everyone needs to post preprints too, so we did that too. First time for me. Anyway, Ali, Antonia, Marius, Stanley and I wrote this manuscript describing Ali and Antonia's work using catalytically inactivate Cas9 to block transcription factor binding at specific sites. This give a quick way to check the function of particular TF binding sites. It works because guide RNAs are longer than TF binding sites so flanking sequence can be used to generate specificity.

Check it out here! https://www.biorxiv.org/content/early/2018/03/15/282681

Posted
AuthorJan Skotheim

A massive thanks to all who attended and made it such a great meeting! From left to right: Amanda Amodeo (Princeton), Peter Pryciak (UMass), Gabriel Neurohr (MIT), Devon Chandler-Brown (Stanford), Fabian Rudolf (ETH), Mimi Xie (Stanford), Me, Matthew Swaffer (Stanford), Daniel Berenson (Stanford), Jon Turner (Stanford), Ben Topacio (Stanford), Ali Shariati (Stanford), Sirle and Mardo Koivomagi (Stanford), Aurora Alvarez-Buylla (Stanford), Kurt Schmoller (Munich), Rob de Bruin (UCL), Evgeny Zatulovskiy (Stanford), Bruce Futcher (SUNY).

Let the field be warned, we are going to get to the bottom on this question!

 

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Posted
AuthorJan Skotheim