TY - JOUR
T1 - ATM Kinase Is Required for Telomere Elongation in Mouse and Human Cells
AU - Lee, Stella Suyong
AU - Bohrson, Craig
AU - Pike, Alexandra Mims
AU - Wheelan, Sarah Jo
AU - Greider, Carol Widney
N1 - Funding Information:
We thank Dr. Mary Armanios, Dr. Stephen Desiderio, and Dr. Jeremy Nathans for critical reading of the manuscript. PacBio sequencing was performed at High Throughput Biology Center at Johns Hopkins University and at the Cold Spring Harbor Laboratory Genome Center, with thanks to Haiping Hao and Eric Antoniou for their assistance. This work was supported by NIH grant R37AG009383 to C.W.G., the Turock Fellowship to S.S.L., and a Commonwealth Foundation Grant to S.J.W.
Publisher Copyright:
© 2015 The Authors.
PY - 2015/11/24
Y1 - 2015/11/24
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2015.10.035
DO - 10.1016/j.celrep.2015.10.035
M3 - Article
C2 - 26586427
AN - SCOPUS:84952874391
SN - 2211-1247
VL - 13
SP - 1623
EP - 1632
JO - Cell Reports
JF - Cell Reports
IS - 8
ER -