Non-canonical MLL1 activity regulates centromeric phase separation and genome stability

Area of Science:

• Molecular Biology
• Epigenetics
• Cancer Biology

Background:

• Epigenetic dysregulation, including mutations in chromatin regulators like MLL/KMT2, is common in cancer.
• While MLL1/KMT2A's role in H3K4 methylation is known, its non-canonical functions are largely uncharacterized.

Purpose of the Study:

• To investigate the unexplored non-canonical activities of MLL1/KMT2A.
• To elucidate MLL1/KMT2A's role in regulating the chromosome passenger complex (CPC) and genome stability.

Main Methods:

• Co-crystal structure analysis of MLL1 SET domain with Borealin.
• Inhibition of MLL1 activity and mutation of Borealin K143.
• Assays for CPC liquid-liquid phase separation, Aurora kinase B activity, kinetochore-microtubule attachments, and sister-chromatid cohesion.

Main Results:

• MLL1/KMT2A directly methylates Borealin K143, essential for CPC phase separation.
• Disruption of this methylation perturbs CPC phase separation, reduces Aurora kinase B activity, and impairs chromosome segregation and cohesion.
• These defects lead to increased chromosome instability and aneuploidy in hepatocellular carcinoma, inhibiting tumor growth.

Conclusions:

• MLL1/KMT2A possesses a non-canonical enzymatic activity essential for regulating inner centromere liquid condensates.
• This function is critical for maintaining genome stability and suppressing tumor growth in certain cancers.