It turns out that intermolecular signaling in epigenetics — all that ubiquination, methylation, and so forth — doesn’t always end at DNA or histones, where those two components go on just to regulate genes (or to encourage more modification of themselves and each other). Nope, John Latham and colleagues at the University of Texas M.D. Anderson Cancer Center reported in Cell last week that there’s at least one case — in yeast — in which a modified histone allows a non-histone protein to methylate another non-histone protein.
That is, the signal travels from the Paf1 complex, to histone H2BK123 by ubiquination, to the COMPASS complex — which needs that ubiquination to di-methylate Dam1. (It’s far more complicated than that, of course. In a related and intertwined pathway, COMPASS also needs a ubiquinated H2BK123 to di- and tri-methylate H3K4, which is itself a common mark of an actively transcribed gene. A whole cast of other cavorting characters also play important parts, including RNA polymerase II, Bur1/Bur2, and Rad/Bre, but that’s way beyond the scope of this post.)
So, what does Dam1 do? Why, it works in a 10-member complex to connect microtubules and kinetochores. In fact, it’s essential to proper chromosome segregation during cell division.
And since it’s involved in cell division, there must be a cancer angle, right? Well, leukemia at least. The central methylator here, the yeast COMPASS complex, contains the key protein Set1, which is orthologous to human MLL proteins. And MLLs are involed in some very similar methylation and complexing of their own. So, to quote Latham and colleagues citing others:
Because MLL is subject to translocations associated with acute leukemias (Berdasco and Esteller, 2010), much research effort is directed toward defining MLL functions. Studies of Set1 in yeast have provided paradigms for understanding the enzymatic activity and regulation of MLL and other H3K4 methyltransferases in higher eukaryotes (Tenney and Shilatifard, 2005).
And a lot of those other characters have human orthologs with connections with cancer too, the authors note, including Ubp8, Rad6 and Bre1, Paf1 complex members, and more. At the end of the paper they add:
Our work raises the possibility that all of these proteins are involved in nontranscriptional processes, such as chromosome segregation, which may also contribute to tumorigenesis, thereby highlighting the importance of defining the full range of functions of these proteins.
And along with a load of other researchers, they’ve pretty well illuminated parts of this crisscrossing pathway, along with an epigenetics first. (I’ll add a diagram to this post soon, if I can get my hands on one.)
(Odd and cool “Semaphore-locusts” photo by Flickr member radioedit used under a Creative Commons license.)
Latham, J., Chosed, R., Wang, S., & Dent, S. (2011). Chromatin Signaling to Kinetochores: Transregulation of Dam1 Methylation by Histone H2B Ubiquitination Cell, 146 (5), 709-719 DOI: 10.1016/j.cell.2011.07.025