9RZC

State 3 MAP 1 SETD2 bound to distal H3 of upstream nucleosome

Summary for 9RZC

• Entry DOI: 10.2210/pdb9rzc/pdb
• EMDB information: 54399
• Descriptor: Non-template DNA, Histone-lysine N-methyltransferase SETD2, Template DNA, ... (8 entities in total)
• Functional Keywords: rna pol ii activated elongation complex co-transcriptional h3k36me3 setd2, transcription
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 12
• Total formula weight: 480712.32

Authors

Walshe, J.L.,Ochmann, M.,Dienemann, C.,Cramer, P. (deposition date: 2025-07-15, release date: 2025-09-24, Last modification date: 2025-11-12)

Primary citation

Walshe, J.L.,Ochmann, M.,Neef, U.,Dybkov, O.,Dienemann, C.,Oberthur, C.,Zheenbekova, A.,Urlaub, H.,Cramer, P.
Molecular mechanism of co-transcriptional H3K36 methylation by SETD2.
Nat Commun, 16:9565-9565, 2025

PubMed Abstract: H3K36me3 is a hallmark of actively and recently transcribed genes and contributes to cellular memory and identity. The deposition of H3K36me3 occurs co-transcriptionally when the methyltransferase SETD2 associates with RNA polymerase II. Here we present three cryo-EM structures of SETD2 bound to RNA polymerase II elongation complexes at different states of nucleosome passage. Together with functional probing, our results suggest a 3-step mechanism of transcription-coupled H3K36me3 deposition. First, binding to the elongation factor SPT6 tethers the catalytic SET domain in proximity to the upstream DNA. Second, RNA polymerase II nucleosome passage leads to the transfer of a hexasome from downstream to upstream, poised for methylation. Finally, continued transcription leads to upstream nucleosome reassembly, partial dissociation of the histone chaperone FACT and sequential methylation of both H3 tails, completing H3K36me3 deposition of an upstream nucleosome after RNA polymerase II passage.

PubMed: 41162378
DOI: 10.1038/s41467-025-65439-y

Experimental method

ELECTRON MICROSCOPY (3.66 Å)