Structure of Telomerase with Telomeric DNA

Jiansen Jiang; Yaqiang Wang; Lukas Sušac; Henry Chan; Ritwika Basu; Z Hong Zhou; Juli Feigon

doi:10.1016/j.cell.2018.04.038

Structure of Telomerase with Telomeric DNA

Cell. 2018 May 17;173(5):1179-1190.e13. doi: 10.1016/j.cell.2018.04.038.

Authors

Jiansen Jiang¹, Yaqiang Wang², Lukas Sušac², Henry Chan², Ritwika Basu², Z Hong Zhou³, Juli Feigon⁴

Affiliations

¹ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: hong.zhou@ucla.edu.
⁴ Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: feigon@mbi.ucla.edu.

Abstract

Telomerase is an RNA-protein complex (RNP) that extends telomeric DNA at the 3' ends of chromosomes using its telomerase reverse transcriptase (TERT) and integral template-containing telomerase RNA (TER). Its activity is a critical determinant of human health, affecting aging, cancer, and stem cell renewal. Lack of atomic models of telomerase, particularly one with DNA bound, has limited our mechanistic understanding of telomeric DNA repeat synthesis. We report the 4.8 Å resolution cryoelectron microscopy structure of active Tetrahymena telomerase bound to telomeric DNA. The catalytic core is an intricately interlocked structure of TERT and TER, including a previously structurally uncharacterized TERT domain that interacts with the TEN domain to physically enclose TER and regulate activity. This complete structure of a telomerase catalytic core and its interactions with telomeric DNA from the template to telomere-interacting p50-TEB complex provides unanticipated insights into telomerase assembly and catalytic cycle and a new paradigm for a reverse transcriptase RNP.

Keywords: CST; IFD; Penelope-like element; TPP1-POT1; group II intron; non-coding RNA; repeat addition processivity; replication protein A; retrotransposase; telomere.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Catalytic Domain
Cryoelectron Microscopy
DNA / chemistry
DNA / metabolism*
Humans
Models, Molecular
Nucleic Acid Conformation
Protein Binding
Protein Subunits / chemistry
Protein Subunits / metabolism
Shelterin Complex
Tartrate-Resistant Acid Phosphatase / metabolism
Telomerase / chemistry
Telomerase / metabolism*
Telomere / chemistry
Telomere / metabolism*
Telomere-Binding Proteins
Tetrahymena thermophila / enzymology
Tetrahymena thermophila / metabolism*

Substances

ACD protein, human
Protein Subunits
Shelterin Complex
Telomere-Binding Proteins
DNA
Telomerase
Tartrate-Resistant Acid Phosphatase

Abstract

Publication types

MeSH terms

Substances

Grants and funding