Recognizing methylated histone variant H3.3 to prevent tumors

Abstract

Regulatory information stored in modified histones is functionally translated by effector proteins ('readers'), which identify the histone mark to determine the specificity of the response. A recent study identifying the tumor suppressor protein ZMYND11 as an exclusive reader of methylated histone variant H3.3, throws light on the role of transcription regulation in suppressing tumors.

Figure 1

(A) Role of H3K36me3 in resetting chromatin. (a) Co-transcriptional addition of H3K36me3 by the lysine methyltransferase Set2 requires association with the elongating polymerase (RNAPII). (b) This mark impedes the ability of histone chaperones (Asf1) to replace existing nucleosomes from the soluble pool. (c) H3K36me3 recruits the chromatin remodeling complex, Isw1b, to coding regions where it acts with Chd1 to maintain chromatin structure. (d) Additionally, H3K36me activates the Rpd3S histone deacetylase complex, resulting in removal of acetyl marks from chromatin over coding regions thereby maintaining a closed chromatin structure. (B) Structure of ZMYND11 interaction domain with H3.3K36me3. Crystal structure of the ZMYND11 Bromodomain-Zinc Finger-PWWP domain fragment (ZMYND11-Bromo-ZnF-PWWP) with each domain color-coded to match with the respective interaction site on the H3.3K36me3 peptide (aa 29-39) shown here. Interestingly, the bromodomain does not contribute additional interactions with the N-terminal tail of the H3.3 peptide. The ribbon model of the protein was prepared using the PDB file 4N4I on the Protein Workshop viewer (PDB).