Disease mutations in the PWWP domain of DNMT3A affect chromatin recruitment through multiple mechanisms

Wapenaar, Hannah, Clifford, Gillian, Taglini, Francesca, McGhie, Finlay ORCID: https://orcid.org/0009-0001-0358-0763, Rolls, Willow, Zhang, Yujie, Sproul, Duncan and Wilson, Marcus D. (2026) Disease mutations in the PWWP domain of DNMT3A affect chromatin recruitment through multiple mechanisms.

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Abstract

DNMT3A is a de novo DNA methyltransferase whose recruitment to chromatin regulates its function. Missense mutations within the chromatin-binding PWWP domain are associated with diverse human disorders, yet how mutations in the same domain produce distinct phenotypes remains unclear. Here we systematically characterise 19 clinically reported mutations in the PWWP domain of DNMT3A that are associated with Heyn-Sproul-Jackson syndrome (HESJAS), paraganglioma (PG) and clonal haematopoiesis (CH). We show that all PWWP-domain mutations associated with HESJAS abolished interaction with H3K36me2 modified nucleosomes, defining this as a consistent biochemical feature of HESJAS. In contrast, mutations from all disease classes differentially altered DNA binding of the PWWP domain, driven by alterations in the net charge of the domain. However, these effects are largely overcome by inclusion of the DNNMT3A1 N-terminal region, which is absent from its embryonic isoform, suggesting that PWWP mutations may differentially affect DNMT3A function through development. Changes in the thermal stability of the isolated PWWP domain mutants did not directly translate into altered stability of full-length DNMT3A1 in cells. We show that HESJAS mutations can affect the intramolecular interaction between the PWWP and adjacent ADD domain, an interaction proposed to contribute to the autoinhibitory function of the ADD domain. However, not all mutations behaved in the same way, suggesting that multiple factors govern the intramolecular autoinhibition of DNMT3A. Together, this study advances our understanding of the molecular mechanisms by which DNMT3A PWWP-domain mutations are mechanistically heterogeneous, providing a biochemical framework that contributes to distinct disease phenotypes.

Item Type:	Article
Uncontrolled Keywords:	sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
UEA Research Groups:	Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry
Depositing User:	LivePure Connector
Date Deposited:	03 Sep 2026 12:54
Last Modified:	06 Sep 2026 23:01
URI:	https://ueaeprints.uea.ac.uk/id/eprint/104410
DOI:	10.64898/2026.08.28.747843

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