Structural mechanisms of DREAM complex assembly and regulation

Area of Science:

• Molecular Biology
• Cell Cycle Regulation
• Structural Biology

Background:

• The DREAM complex (DPP107/130-RB-E2F-MuvB) represses cell cycle genes during quiescence.
• Upon cell cycle entry, MuvB dissociates from p107/p130 and recruits B-Myb and FoxM1 to promote mitosis.

Purpose of the Study:

• To elucidate the structural mechanisms governing DREAM complex assembly and regulation.
• To understand how viral oncoproteins disrupt the DREAM complex.

Main Methods:

• Investigated the structural basis for DREAM complex assembly.
• Determined the crystal structure of the LIN52-p107 complex.
• Analyzed the binding interactions and phosphorylation-dependent regulation of DREAM components.

Main Results:

• Identified a LIN52 sequence that binds phosphorylated p107 and p130 pocket domains.
• The crystal structure revealed high-affinity binding of LIN52 to p107 via a suboptimal LxSxExL motif and phosphorylation at S28.
• Demonstrated that cyclin-dependent kinase phosphorylation of p130 weakens its association with MuvB, facilitating DREAM disassembly.

Conclusions:

• The structural insights explain DREAM complex specificity for p107/p130 over Rb and disruption by viral oncoproteins.
• Discovered a novel target interface for studying MuvB and p130 function.
• Informs the design of inhibitors to prevent tumor cell escape from quiescence.