Histone methyltransferases regulate chromatin organization and are frequently mutated in human diseases, including cancer. One such often mutated methyltransferase, SETD2, associates with transcribing RNA polymerase II and catalyses H3K36me3-a modification that contributes to gene transcription, splicing and DNA repair. Although its catalytic function is well-characterized, its non-catalytic roles remain unclear. Here we reveal a catalysis-independent function of SETD2 in nuclear lamina stability and genome integrity. Through its intrinsically disordered amino terminus, SETD2 associates with lamina-associated proteins, including lamin A/C, lamin B1 and emerin. Loss of SETD2 or its N terminus leads to severe nuclear morphology defects and genome instability, mirroring lamina dysfunction. Mechanistically, the N terminus of SETD2 serves as a scaffold for the mitotic kinase CDK1 and lamins, facilitating lamin phosphorylation and depolymerization during mitosis. Restoration of the N-terminal regions required for interaction with CDK1 and lamins rescues nuclear morphology and suppresses tumorigenic growth in a clear cell renal cell carcinoma model with SETD2 haploinsufficiency. These findings reveal a previously unrecognized role of SETD2 in nuclear lamina organization and genome maintenance that probably extends to its role as a tumour suppressor.
© 2025. The Author(s), under exclusive licence to Springer Nature Limited.