CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci

Donald P. Cameron; Jirawas Sornkom; Sameerh Alsahafi; Denis Drygin; Gretchen Poortinga; Grant A. McArthur; Nadine Hein; Ross Hannan; Konstantin I. Panov

doi:10.3390/biomedicines12071514

CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci

Donald P. Cameron, Jirawas Sornkom, Sameerh Alsahafi, Denis Drygin, Gretchen Poortinga, Grant A. McArthur, Nadine Hein, Ross Hannan^*, Konstantin I. Panov^*

^*Corresponding author for this work

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Abstract

While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.

Original language	English
Article number	1514
Journal	Biomedicines
Volume	12
Issue number	7
DOIs	https://doi.org/10.3390/biomedicines12071514
Publication status	Published - 08 Jul 2024

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CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci
Copyright 2024 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
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Cite this

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title = "CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci",

abstract = "While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.",

author = "Cameron, {Donald P.} and Jirawas Sornkom and Sameerh Alsahafi and Denis Drygin and Gretchen Poortinga and McArthur, {Grant A.} and Nadine Hein and Ross Hannan and Panov, {Konstantin I.}",

year = "2024",

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doi = "10.3390/biomedicines12071514",

language = "English",

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T1 - CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci

AU - Cameron, Donald P.

AU - Sornkom, Jirawas

AU - Alsahafi, Sameerh

AU - Drygin, Denis

AU - Poortinga, Gretchen

AU - McArthur, Grant A.

AU - Hein, Nadine

AU - Hannan, Ross

AU - Panov, Konstantin I.

PY - 2024/7/8

Y1 - 2024/7/8

N2 - While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.

AB - While genotoxic chemotherapeutic agents are among the most effective tools to combat cancer, they are often associated with severe adverse effects caused by indiscriminate DNA damage in non-tumor tissue as well as increased risk of secondary carcinogenesis. This study builds on our previous work demonstrating that the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 elicits a non-canonical DNA damage response and our discovery of a critical role for Topoisomerase 2α (Top2α) in the initiation of Pol I-dependent transcription. Here, we identify Top2α as a mediator of CX-5461 response in the murine Eµ-Myc B lymphoma model whereby sensitivity to CX-5461 is dependent on cellular Top2α expression/activity. Most strikingly, and in contrast to canonical Top2α poisons, we found that the Top2α-dependent DNA damage induced by CX-5461 is preferentially localized at the ribosomal DNA (rDNA) promoter region, thereby highlighting CX-5461 as a loci-specific DNA damaging agent. This mechanism underpins the efficacy of CX-5461 against certain types of cancer and can be used to develop effective non-genotoxic anticancer drugs.

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DO - 10.3390/biomedicines12071514

M3 - Article

SN - 2227-9059

VL - 12

JO - Biomedicines

JF - Biomedicines

IS - 7

M1 - 1514

ER -

CX-5461 preferentially induces Top2α-dependent DNA breaks at ribosomal DNA loci

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