ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

Stella Suyong Lee; Craig Bohrson; Alexandra Mims Pike; Sarah Jo Wheelan; Carol Widney Greider

doi:10.1016/j.celrep.2015.10.035

ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells

Cell Rep. 2015 Nov 24;13(8):1623-32. doi: 10.1016/j.celrep.2015.10.035. Epub 2015 Nov 12.

Authors

Stella Suyong Lee¹, Craig Bohrson², Alexandra Mims Pike³, Sarah Jo Wheelan⁴, Carol Widney Greider⁵

Affiliations

¹ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Predoctoral Training Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Predoctoral Training Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁵ Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Predoctoral Training Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: cgreider@jhmi.edu.

Abstract

Short telomeres induce a DNA damage response, senescence, and apoptosis, thus maintaining telomere length equilibrium is essential for cell viability. Telomerase addition of telomere repeats is tightly regulated in cells. To probe pathways that regulate telomere addition, we developed the ADDIT assay to measure new telomere addition at a single telomere in vivo. Sequence analysis showed telomerase-specific addition of repeats onto a new telomere occurred in just 48 hr. Using the ADDIT assay, we found that ATM is required for addition of new repeats onto telomeres in mouse cells. Evaluation of bulk telomeres, in both human and mouse cells, showed that blocking ATM inhibited telomere elongation. Finally, the activation of ATM through the inhibition of PARP1 resulted in increased telomere elongation, supporting the central role of the ATM pathway in regulating telomere addition. Understanding this role of ATM may yield new areas for possible therapeutic intervention in telomere-mediated disease.

Publication types

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

MeSH terms

Animals
Ataxia Telangiectasia Mutated Proteins / metabolism*
Cell Cycle Proteins / metabolism
Cell Line
DNA-Binding Proteins / metabolism
Humans
Mice
Poly(ADP-ribose) Polymerases / metabolism
Telomerase / metabolism
Telomere / metabolism*

Substances

Cell Cycle Proteins
DNA-Binding Proteins
Poly(ADP-ribose) Polymerases
Ataxia Telangiectasia Mutated Proteins
Telomerase

Associated data

SRA/SRP059426

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding