Cryo-EM structure of substrate-bound human telomerase holoenzyme

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Telomerase maintains chromosome ends but its dysregulation is linked to cancer, disease, and aging.
• Lack of structural data has hindered clinical manipulation of telomerase.
• Understanding telomerase structure is vital for therapeutic development.

Purpose of the Study:

• To determine the high-resolution structure of the substrate-bound human telomerase holoenzyme.
• To provide a structural basis for understanding telomerase function and disease-related mutations.
• To facilitate the development of novel telomerase-based therapeutics.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to visualize the human telomerase holoenzyme.
• Subnanometer resolution structural analysis was performed on the substrate-bound enzyme.
• Computational modeling and analysis were employed to interpret the structural data.

Main Results:

• The structure reveals two flexibly RNA-tethered lobes: a catalytic core and an H/ACA ribonucleoprotein (RNP) complex.
• The catalytic core contains telomerase reverse transcriptase (TERT) and conserved telomerase RNA (hTR) motifs, with RNA encircling TERT.
• The H/ACA RNP lobe includes H/ACA proteins and TCAB1, offering insights into RNP biogenesis.

Conclusions:

• The presented structure provides a foundational framework for understanding human telomerase.
• This structural insight is crucial for interpreting disease mutations affecting telomerase function.
• The findings represent a significant advancement towards developing clinical therapeutics targeting telomerase.