A SETD2-CDK1-lamin axis maintains nuclear morphology and genome stability

Area of Science:

• Molecular Biology
• Cell Biology
• Cancer Research

Background:

• Histone methyltransferases regulate chromatin and are implicated in cancer.
• SETD2 catalyzes H3K36me3, impacting transcription, splicing, and DNA repair.
• The non-catalytic functions of SETD2 are not well understood.

Purpose of the Study:

• To investigate the non-catalytic roles of SETD2.
• To elucidate SETD2's function in nuclear lamina stability and genome integrity.

Main Methods:

• Studied SETD2's interaction with lamina-associated proteins using its N-terminus.
• Examined nuclear morphology and genome instability in SETD2-deficient cells.
• Investigated SETD2's role as a scaffold for CDK1 and lamins during mitosis.
• Utilized a clear cell renal cell carcinoma model.

Main Results:

• SETD2's N-terminus interacts with lamin A/C, lamin B1, and emerin.
• Loss of SETD2 or its N-terminus causes nuclear defects and genome instability.
• SETD2 scaffolds CDK1 and lamins, promoting lamin phosphorylation and depolymerization during mitosis.
• Restoring SETD2's N-terminal interactions rescues nuclear morphology and suppresses tumor growth in a cancer model.

Conclusions:

• SETD2 has a critical catalysis-independent function in maintaining nuclear lamina stability and genome integrity.
• This function is mediated by the SETD2 N-terminus, which interacts with lamina proteins and mitotic kinase CDK1.
• SETD2's role in nuclear organization contributes to its tumor suppressor activity.