SETD2-Mediated Microtubule Methylation Prevents Genomic Instability

A number of “histone code” readers, writers, and erasers have been described which post-translationally modify histone tails to mediate chromatin remodeling. The SET-domain-containing 2 (SETD2) histone methyltransferase is an example of a histone code writer that trimethylates histone H3 lysine 36 (H3K36me3) to promote gene transcription. Similarly, an analogous “tubulin code” has been proposed in which post-translational modifications modulate the function of subsets of microtubules in the cytoskeleton. Microtubules are made up of heterodimers of α- and β-tubulin that form the mitotic spindle during cell division, but the role of post-translational modifications in this process remains largely unknown. Thus far, the identified readers, writers, and erasers of the histone and tubulin codes are distinct; however, Park, Powell, and colleagues demonstrated that SETD2 has a dual role in both histone and tubulin methylation. The SET domain of SETD2 bound to and trimethylated lysine 40 of α-tubulin (α-tubK40me3) during mitosis. This residue can also be acetylated, but methylation of K40 was independent of acetylation. Consistent with the role of SETD2 in methylating α-tubulin, depletion of SETD2 resulted in loss of α-tubK40me3. Further, cells lacking SETD2 took longer to complete mitosis, often failed to undergo cytokinesis, and exhibited increased polyploidy, indicating an increase in genomic instability. SETD2 loss induced mitotic defects, including failure of chromosomes to align at the spindle equator, increased multipolar spindles at prometaphase, lagging chromosomes at anaphase, and chromosomal bridges at cytokinesis. The mitotic and cytokinesis defects caused by SETD2 loss were independent of SETD2-dependent histone methylation, confirming that α-tubulin methylation is responsible for the observed genomic instability. In addition to elucidating a role for SETD2 in methylating microtubules to promote normal mitosis and cytokinesis, these findings reveal a dual role for SETD2 in chromatin and cytoskeletal remodeling and cross-talk between the histone and tubulin codes.

Park IY, Powell RT, Tripathi DN, Dere R, Ho TH, Blasius TL, et al. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 2016;166:950–62.