Khan Abid, Zhang Cheng, Nguyen Phu G, Metts James M, Collins Lucas C, Jain Kanishk, Mills C Allie, Vlach Logan, Li Kelin, Brademeyer Amanda L, Bowman Brittany M, Major Michael B, Aubé Jeffrey, Herring Laura E, Rathmell W Kimryn, Mason Frank M, Davis Ian J, Zhang Qing, Strahl Brian D
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
Nat Cell Biol. 2025 Aug;27(8):1327-1341. doi: 10.1038/s41556-025-01723-9. Epub 2025 Aug 11.
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.
组蛋白甲基转移酶调节染色质组织，且在包括癌症在内的人类疾病中经常发生突变。其中一种经常发生突变的甲基转移酶SETD2，与正在转录的RNA聚合酶II相关联，并催化H3K36me3——一种有助于基因转录、剪接和DNA修复的修饰。尽管其催化功能已得到充分表征，但其非催化作用仍不清楚。在这里，我们揭示了SETD2在核纤层稳定性和基因组完整性方面的非催化功能。通过其内在无序的氨基末端，SETD2与包括核纤层蛋白A/C、核纤层蛋白B1和emerin在内的核纤层相关蛋白相关联。SETD2或其N末端的缺失会导致严重的核形态缺陷和基因组不稳定，这与核纤层功能障碍相似。从机制上讲，SETD2的N末端作为有丝分裂激酶CDK1和核纤层蛋白的支架，促进有丝分裂期间核纤层蛋白的磷酸化和解聚。在具有SETD2单倍体不足的透明细胞肾细胞癌模型中，恢复与CDK1和核纤层蛋白相互作用所需的N末端区域可挽救核形态并抑制肿瘤生长。这些发现揭示了SETD2在核纤层组织和基因组维持中以前未被认识的作用，这可能扩展到其作为肿瘤抑制因子的作用。
