Cell-cell adhesion regulates Merlin/NF2 interaction with the PAF complex

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• The PAF complex (PAFC) regulates transcription elongation and mRNA processing, with its CDC73/parafibromin subunit acting as a tumor suppressor.
• The NF2/Merlin tumor suppressor is involved in contact inhibition, but its nuclear functions and molecular mechanisms are not fully understood.

Purpose of the Study:

• To identify novel Merlin-interacting proteins using affinity proteomics.
• To elucidate the molecular mechanisms underlying Merlin's role in contact inhibition and its relationship with the PAF complex.

Main Methods:

• Affinity proteomics to identify Merlin-interacting proteins.
• Analysis of tumor-derived mutations in Merlin and CDC73.
• Investigation of cell density-dependent interactions and the role of FAT cadherins.

Main Results:

• Merlin forms a complex with RNA processing proteins, including the PAFC and CHD1 chromatin remodeler.
• Tumor-associated mutations in Merlin and CDC73 disrupt their interaction.
• Merlin's growth suppression activity requires CDC73, and its interaction with PAFC is regulated by cell density and FAT cadherins.

Conclusions:

• Merlin functions as part of a tumor suppressor network linked to cell-cell adhesion and transcription regulation.
• This network coordinates post-initiation transcription steps for genes involved in contact inhibition.
• Merlin's role extends beyond the Hippo pathway, involving coordination of transcription and mRNA processing.