Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites

Joyce H. Lee; Eric P. Mosher; Young Sam Lee; Namandjé N. Bumpus; James M. Berger

doi:10.1016/j.chembiol.2021.08.014

Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites

Joyce H. Lee
, Eric P. Mosher
, Young Sam Lee
, Namandjé N. Bumpus
, James M. Berger

Producción científica: Article › revisión exhaustiva

15 Citas (Scopus)

Resumen

Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.

Idioma original	English
Páginas (desde-hasta)	476-489.e6
Publicación	Cell Chemical Biology
Volumen	29
N.º	3
DOI	https://doi.org/10.1016/j.chembiol.2021.08.014
Estado	Published - mar 17 2022

Nota bibliográfica

Publisher Copyright:
© 2021 Elsevier Ltd

Financiación

We thank B. Cormack and members of C. Wolberger’s lab for access to and guidance on the usage of equipment employed for this study. We thank M. Bjornsti for sharing the ED yeast strain, G. Hauk for providing purified E. coli topo IV, and J. Jeong for help in preparing S. cerevisiae topo I. We are grateful to J. Stivers, B. Cormack, J. Nitiss, and T. Lee for advice, as well as M. Wolfgang and S. Yegnasubramanian for critical reading of the manuscript. These studies were supported by the NIH ( T32-GM007445 and F31-CA224896 to J.L., R01-CA168653 to Y.-S.L., R01-GM103853 to N.N.B., and R01-CA077373 to J.M.B.). The data obtained in this study is accessible at the NIH Common Fund's NMDR (supported by NIH grant, U01-DK097430) website, the Metabolomics Workbench ( Sud et al., 2016 ), MW: https://doi.org/10.21228/M89695 . This paper does not report original code. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Financiadores	Número del financiador
Metabolomics Workbench
National Institutes of Health (NIH)	F31-CA224896, R01-GM103853, R01-CA168653, R01-CA077373, U01-DK097430
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	T32GM007445

ODS de las Naciones Unidas

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Good health and well being

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmacology
Drug Discovery
Clinical Biochemistry

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title = "Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites",

abstract = "Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.",

keywords = "DNA topology, ICRF-187, TCA cycle, cancer, chemotherapy, dexrazoxane, etoposide, metabolism, topoisomerase",

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AU - Mosher, Eric P.

AU - Lee, Young Sam

AU - Bumpus, Namandjé N.

AU - Berger, James M.

PY - 2022/3/17

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N2 - Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.

AB - Topoisomerase II (topo II) is essential for disentangling newly replicated chromosomes. DNA unlinking involves the physical passage of one duplex through another and depends on the transient formation of double-stranded DNA breaks, a step exploited by frontline chemotherapeutics to kill cancer cells. Although anti-topo II drugs are efficacious, they also elicit cytotoxic side effects in normal cells; insights into how topo II is regulated in different cellular contexts is essential to improve their targeted use. Using chemical fractionation and mass spectrometry, we have discovered that topo II is subject to metabolic control through the TCA cycle. We show that TCA metabolites stimulate topo II activity in vitro and that levels of TCA flux modulate cellular sensitivity to anti-topo II drugs in vivo. Our work reveals an unanticipated connection between the control of DNA topology and cellular metabolism, a finding with ramifications for the clinical use of anti-topo II therapies.

KW - DNA topology

KW - ICRF-187

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KW - cancer

KW - chemotherapy

KW - dexrazoxane

KW - etoposide

KW - metabolism

KW - topoisomerase

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Control of topoisomerase II activity and chemotherapeutic inhibition by TCA cycle metabolites

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