Human RPA is an essential telomerase processivity factor for maintaining telomeres

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Telomeres protect chromosome ends from degradation and fusion.
• Telomerase is a reverse transcriptase that maintains telomere length.
• Telomere shortening is associated with cellular aging and diseases.

Purpose of the Study:

• To investigate the role of Replication Protein A (RPA) in telomere maintenance.
• To elucidate the mechanism by which RPA interacts with telomerase.
• To explore the link between RPA function and telomeropathies.

Main Methods:

• In vitro biochemical assays to measure telomerase processivity.
• AlphaFold modeling to predict protein-protein interactions.
• Engineering of telomerase reverse transcriptase (TERT) mutants.
• Analysis of telomerase activity in disease-associated mutants.

Main Results:

• RPA acts as a critical processivity factor for telomerase.
• AlphaFold modeling suggests RPA binds a distinct site on TERT compared to TPP1.
• TERT mutants lacking RPA-mediated stimulation show impaired telomere elongation.
• Short-telomere disease-associated TERT mutations exhibit reduced RPA-dependent stimulation.

Conclusions:

• Human RPA is a key regulator of telomerase activity and processivity.
• Impaired RPA-telomerase interaction contributes to telomeropathies.
• These findings provide molecular insights into telomere maintenance and related diseases.