SETD2 Maintains Nuclear Integrity Through Mitotic Lamin Phosphorylation

SETD2 is a histone-modifying enzyme that is widely studied for its role in histone H3 lysine 36 trimethylation (H3K36me3), which is responsible for vital cellular processes such as DNA repair, chromatin organization, and transcription regulation. Interestingly, SETD2 is mutated in 15% of clear cell renal cell carcinomas (ccRCC) and 13% of endometrial carcinomas. However, the mechanism by which loss of SETD2 contributes to cancer development is poorly understood. Furthermore, does the tumor suppressor role of SETD2 depend on its catalytic activity? To answer this question, we first mapped SETD2’s protein interactome and found that, surprisingly, it interacts with components of the nuclear lamina – a filamentous meshwork of lamin proteins at the nuclear periphery that directly controls nuclear and genome integrity. Consequently, the loss of SETD2 resulted in nuclear and genome integrity defects that were reminiscent of a defective nuclear lamina. Surprisingly, inhibition of SETD2’s catalytic activity did not produce these defects, indicating a novel non-catalytic role for SETD2 in maintaining nuclear and genome stability. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Finally, we found that this N-terminal region of SETD2 can inhibit tumorigenic growth in a SETD2 haploinsufficient model of ccRCC. Our findings reveal an unanticipated link between SETD2 and nuclear lamina organization that may underlie how SETD2 contributes as a tumor suppressor in ccRCC.