Structure of Telomerase with Telomeric DNA

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Telomerase is a crucial RNA-protein complex (RNP) responsible for extending telomeric DNA.
• Its activity impacts aging, cancer, and stem cell renewal.
• A lack of atomic models, especially with bound DNA, has hindered mechanistic understanding.

Purpose of the Study:

• To determine the atomic structure of active telomerase bound to telomeric DNA.
• To elucidate the mechanistic details of telomeric DNA repeat synthesis.

Main Methods:

• Cryoelectron microscopy (cryo-EM) was used to determine the structure.
• The structure was resolved at 4.8 Å resolution.

Main Results:

• The catalytic core of Tetrahymena telomerase bound to telomeric DNA was visualized.
• An intricately interlocked structure of telomerase reverse transcriptase (TERT) and telomerase RNA (TER) was revealed.
• A novel TERT domain interacting with the TEN domain to enclose TER and regulate activity was identified.

Conclusions:

• The complete structure provides unprecedented insights into telomerase assembly and its catalytic cycle.
• This work establishes a new paradigm for reverse transcriptase RNPs.
• Understanding telomerase structure is key to targeting age-related diseases and cancer.