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

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 tha...

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Autores principales:	Chiaki Fujiwara, Yukiko Muramatsu, Megumi Nishii, Kazuhiro Tokunaka, Hidetoshi Tahara, Masaru Ueno, Takao Yamori, Yoshikazu Sugimoto, Hiroyuki Seimiya
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Telomerase Inhibition Telomerase Activity Acute Deleterious Effects Telomere Shortening Hutchinson-Gilford Progeria Syndrome (HGPS) Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bcff0d57a37a40e7bac59241a17f8c5f
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spelling	oai:doaj.org-article:bcff0d57a37a40e7bac59241a17f8c5f2021-12-02T11:40:54ZCell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells10.1038/s41598-018-33139-x2045-2322https://doaj.org/article/bcff0d57a37a40e7bac59241a17f8c5f2018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33139-xhttps://doaj.org/toc/2045-2322Abstract 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.Chiaki FujiwaraYukiko MuramatsuMegumi NishiiKazuhiro TokunakaHidetoshi TaharaMasaru UenoTakao YamoriYoshikazu SugimotoHiroyuki SeimiyaNature PortfolioarticleTelomerase InhibitionTelomerase ActivityAcute Deleterious EffectsTelomere ShorteningHutchinson-Gilford Progeria Syndrome (HGPS)MedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-15 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Telomerase Inhibition Telomerase Activity Acute Deleterious Effects Telomere Shortening Hutchinson-Gilford Progeria Syndrome (HGPS) Medicine R Science Q
spellingShingle	Telomerase Inhibition Telomerase Activity Acute Deleterious Effects Telomere Shortening Hutchinson-Gilford Progeria Syndrome (HGPS) Medicine R Science Q Chiaki Fujiwara Yukiko Muramatsu Megumi Nishii Kazuhiro Tokunaka Hidetoshi Tahara Masaru Ueno Takao Yamori Yoshikazu Sugimoto Hiroyuki Seimiya Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
description	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.
format	article
author	Chiaki Fujiwara Yukiko Muramatsu Megumi Nishii Kazuhiro Tokunaka Hidetoshi Tahara Masaru Ueno Takao Yamori Yoshikazu Sugimoto Hiroyuki Seimiya
author_facet	Chiaki Fujiwara Yukiko Muramatsu Megumi Nishii Kazuhiro Tokunaka Hidetoshi Tahara Masaru Ueno Takao Yamori Yoshikazu Sugimoto Hiroyuki Seimiya
author_sort	Chiaki Fujiwara
title	Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
title_short	Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
title_full	Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
title_fullStr	Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
title_full_unstemmed	Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells
title_sort	cell-based chemical fingerprinting identifies telomeres and lamin a as modifiers of dna damage response in cancer cells
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/bcff0d57a37a40e7bac59241a17f8c5f
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Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells

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