Peptides Targeting the Interaction Between Erb1 and Ytm1 Ribosome Assembly Factors

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• Ribosome biogenesis is crucial for cancer cell proliferation and is an emerging therapeutic target.
• Cancer cells exhibit heightened sensitivity to ribosome production inhibition compared to healthy cells.
• Current strategies targeting RNA Polymerase I (RNA Pol I) face limitations such as lack of specificity and acquired resistance.

Purpose of the Study:

• To explore novel therapeutic strategies by targeting downstream steps in ribosome biogenesis.
• To identify and develop interference peptides that disrupt essential protein-protein interactions between ribosome assembly factors.
• To validate the binding capability of selected peptides to their cellular partners using biophysical methods.

Main Methods:

• Utilized a crystal structure of the *Chaetomium thermophilum* complex (Erb1 and Ytm1) for structure-guided peptide selection.
• Employed mutagenesis studies to understand the impact of altered assembly factor interfaces on ribosome maturation.
• Applied biophysical techniques to assess the *in vitro* binding affinity of interference peptides to their target partners.

Main Results:

• Successfully designed and selected interference peptides based on the Erb1-Ytm1 complex structure.
• Demonstrated the *in vitro* ability of these peptides to bind their intended cellular partners.
• Established a foundation for developing novel ribosome biogenesis inhibitors.

Conclusions:

• Targeting protein-protein interactions among ribosome assembly factors offers a promising alternative to inhibiting transcription.
• Interference peptides derived from structural insights can serve as tools to modulate ribosome biogenesis.
• This research paves the way for developing new anti-cancer drugs that exploit cancer cells' dependency on ribosome production.