Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells

Chiaki Fujiwara, Yukiko Muramatsu, Megumi Nishii, Kazuhiro Tokunaka, Hidetoshi Tahara, Masaru Ueno, Takao Yamori, Yoshikazu Sugimoto, Hiroyuki Seimiya

Research output: Contribution to journalArticle

Abstract

Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.

Original languageEnglish
Article number14827
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Lamin Type A
Telomere
DNA Damage
Telomerase
Neoplasms
Nuclear Lamina
Apoptosis
Topoisomerase II Inhibitors
Telomere Shortening
Double-Stranded DNA Breaks
Nuclear Proteins
Antineoplastic Agents
Maintenance
MST 312
DNA
Growth

ASJC Scopus subject areas

  • General

Cite this

Fujiwara, C., Muramatsu, Y., Nishii, M., Tokunaka, K., Tahara, H., Ueno, M., ... Seimiya, H. (2018). Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. Scientific Reports, 8(1), [14827]. https://doi.org/10.1038/s41598-018-33139-x

Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. / Fujiwara, Chiaki; Muramatsu, Yukiko; Nishii, Megumi; Tokunaka, Kazuhiro; Tahara, Hidetoshi; Ueno, Masaru; Yamori, Takao; Sugimoto, Yoshikazu; Seimiya, Hiroyuki.

In: Scientific Reports, Vol. 8, No. 1, 14827, 01.12.2018.

Research output: Contribution to journalArticle

Fujiwara, C, Muramatsu, Y, Nishii, M, Tokunaka, K, Tahara, H, Ueno, M, Yamori, T, Sugimoto, Y & Seimiya, H 2018, 'Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells', Scientific Reports, vol. 8, no. 1, 14827. https://doi.org/10.1038/s41598-018-33139-x
Fujiwara, Chiaki ; Muramatsu, Yukiko ; Nishii, Megumi ; Tokunaka, Kazuhiro ; Tahara, Hidetoshi ; Ueno, Masaru ; Yamori, Takao ; Sugimoto, Yoshikazu ; Seimiya, Hiroyuki. / Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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