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Transient telomere dysfunction induces chromosomal instability and promotes carcinogenesis
Yvonne Begus-Nahrmann, Daniel Hartmann, Johann Kraus, Parisa Eshraghi, Annika Scheffold, Melanie Grieb, Volker Rasche, Peter Schirmacher, Han-Wong Lee, Hans A. Kestler, André Lechel, and K. Lenhard Rudolph
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Published January 4, 2021 - More info
J Clin Invest. 2021;131(1):e145852. https://doi.org/10.1172/JCI145852.
© 2021 American Society for Clinical Investigation
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Abstract
Telomere shortening limits the proliferative capacity of a cell, but perhaps surprisingly, shortening is also known to be associated with increased rates of tumor initiation. A current hypothesis suggests that telomere dysfunction increases tumor initiation by induction of chromosomal instability, but that initiated tumors need to reactivate telomerase for genome stabilization and tumor progression. This concept has not been tested in vivo, since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis in a mouse model of inducible telomere dysfunction on a telomerase-proficient background, in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc–/–), and in WT mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell-cycle arrest, and apoptosis in telomerase-deficient liver tumors. Together, these data provide in vivo evidence that transient telomere dysfunction during early or late stages of tumorigenesis promotes chromosomal instability and carcinogenesis in telomerase-proficient mice.
Authors
Yvonne Begus-Nahrmann, Daniel Hartmann, Johann Kraus, Parisa Eshraghi, Annika Scheffold, Melanie Grieb, Volker Rasche, Peter Schirmacher, Han-Wong Lee, Hans A. Kestler, André Lechel, K. Lenhard Rudolph
Original citation: J Clin Invest. 2012;122(6):2283–2288. https://doi.org/10.1172/JCI61745
Citation for this corrigendum: J Clin Invest. 2021;131(1):e145852. https://doi.org/10.1172/JCI145852
In some figures, sample sizes were omitted or incorrectly stated. Data shown in Figure 2, A–C, and Supplemental Figure 5, A–C, were from the same experiment, which, as indicated, included male and female mice. The correct sample sizes for those figures are as follows: male mice: TTD+ liver, n = 3; TTD+ HCC, n = 5; TTD– liver, n = 5; TTD– HCC, n = 6; G3 HCC, n = 5; female mice: TTD+ liver, n = 6; TTD+ HCC, n = 5; TTD– liver, n = 6; TTD– HCC, n = 4. The correct sample sizes for Figure 3E are as follows: TTD+ liver, n = 7; TTD+ HCC, n = 4; TTD– liver, n = 12; TTD– HCC, n = 11; G3 HCC, n = 5. The correct sample sizes for Supplemental Figure 5D are as follows: TTD+, n = 5; TTD–, n = 3; G3, n = 5. The correct sample sizes for Supplemental Figure 8, C and D, are as follows: n = 4 per group. Supplemental Figure 5D showed error bars as SD instead of SEM, as stated in Methods, and there were errors in the depictions of P values. Both are corrected the revised Supplemental Figure 5D, which is shown below and has been replaced in the supplemental data file. In Supplemental Figure 1E, Western blots for detecting TRF2ΔBΔM and GAPDH were run on separate gels using the same lysates. The authors have stated that the described corrections do not change any of the conclusions of the article.
The authors regret the errors.
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