美国北卡罗来纳大学Brian D. Strahl研究组近日取得一项新成果。经过不懈努力，他们提出了SETD2–CDK1-纤层蛋白轴维持核形态和基因组稳定性。相关论文于2025年8月11日发表在《自然—细胞生物学》杂志上。

在这里，课题组揭示了SETD2在核层稳定性和基因组完整性中的催化独立功能。通过其内在无序的氨基末端，SETD2与层相关蛋白结合，包括层粘连蛋白A/C、层粘连蛋白B1和emerin。SETD2或其N端缺失会导致严重的核形态缺陷和基因组不稳定，反映出板层功能障碍。从机制上讲，SETD2的N端作为有丝分裂激酶CDK1和层粘连蛋白的支架，促进有丝分裂过程中层粘连蛋白的磷酸化和解聚。在SETD2单倍体功能不全的透明细胞肾细胞癌模型中，恢复与CDK1和层蛋白相互作用所需的N端区域可恢复核形态并抑制致瘤性生长。这些发现揭示了先前未被认识到的SETD2在核层组织和基因组维持中的作用，可能延伸到其作为肿瘤抑制因子的作用。

研究人员表示，组蛋白甲基转移酶调节染色质组织，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与转录RNA聚合酶II相关，并催化H3K36me3-a修饰，这种修饰有助于基因转录、剪接和DNA修复。虽然其催化功能已被很好地表征，但其非催化作用仍不清楚。

附：英文原文

Title: A SETD2–CDK1–lamin axis maintains nuclear morphology and genome stability

Author: 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., Aub, Jeffrey, Herring, Laura E., Rathmell, W. Kimryn, Mason, Frank M., Davis, Ian J., Zhang, Qing, Strahl, Brian D.

Issue&Volume: 2025-08-11

Abstract: 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.

DOI: 10.1038/s41556-025-01723-9

Source: https://www.nature.com/articles/s41556-025-01723-9