Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L

Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L

Two scientists have unraveled aspects of how DNA organizes and preserves genetic information.

To turn genes in DNA "on" and "off," enzymes in cells must interact with nucleosomes, which are complexes containing proteins that allow cells to organize their DNA. One such enzyme, Dot1L, a methytransferase, is mutated in mixed lineage leukemia, a form of childhood leukemia.

A small protein tag called ubiquitin must first be attached to nucleosomes in order to help recruit Dot1L. However, how the Dot1L enzyme physically connects with the nucleosome or with the ubiquitin tag was not clear until the researchers used an imaging tool called cryogenic electron microscopy (cryo-EM) to freeze molecules in a nucleosome and Dot1L to see how the two interact.

What they found in the study, which was published in Cell, was unexpected: Dot1L changes the shape of the nucleosome to bind more closely with the Dot1L enzyme.

The high-resolution images taken with cryo-EM revealed a dramatic never-before-seen change in the core of the nucleosome. As Dot1L connected, a H4 tail from the center of the nucleosome swung up to secure the enzyme to its surface, causing a cascade of other changes in the nucleosome's structure. The contacts mediated by Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to insert into the active site in a position primed for catalysis.

This observation, say the researchers, represents a paradigm shift in how we think about genetic illness, as changes in the nucleosome structure impact how our cells access their DNA. "It opens new doors for discovery we didn't even know were there," says the senior author.

Specifically for childhood leukemia, the discovery of how the nucleosome changes shape to make a good fit with Dot1L could unveil opportunities to find new treatments targeting that connection.