Topoisomerase II poisons inhibit vertebrate DNA replication through distinct mechanisms.
DNA Damage
DNA replication
cancer
chemotherapy
topoisomerase
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
14 06 2022
14 06 2022
Historique:
revised:
25
04
2022
received:
10
01
2022
accepted:
28
04
2022
pubmed:
18
5
2022
medline:
16
6
2022
entrez:
17
5
2022
Statut:
ppublish
Résumé
Topoisomerase II (TOP2) unlinks chromosomes during vertebrate DNA replication. TOP2 "poisons" are widely used chemotherapeutics that stabilize TOP2 complexes on DNA, leading to cytotoxic DNA breaks. However, it is unclear how these drugs affect DNA replication, which is a major target of TOP2 poisons. Using Xenopus egg extracts, we show that the TOP2 poisons etoposide and doxorubicin both inhibit DNA replication through different mechanisms. Etoposide induces TOP2-dependent DNA breaks and TOP2-dependent fork stalling by trapping TOP2 behind replication forks. In contrast, doxorubicin does not lead to appreciable break formation and instead intercalates into parental DNA to stall replication forks independently of TOP2. In human cells, etoposide stalls forks in a TOP2-dependent manner, while doxorubicin stalls forks independently of TOP2. However, both drugs exhibit TOP2-dependent cytotoxicity. Thus, etoposide and doxorubicin inhibit DNA replication through distinct mechanisms despite shared genetic requirements for cytotoxicity.
Identifiants
pubmed: 35578785
doi: 10.15252/embj.2022110632
pmc: PMC9194788
doi:
Substances chimiques
Poisons
0
Etoposide
6PLQ3CP4P3
Doxorubicin
80168379AG
DNA
9007-49-2
DNA Topoisomerases, Type II
EC 5.99.1.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e110632Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM128696
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM126363
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA239161
Pays : United States
Organisme : NIGMS NIH HHS
ID : F32 GM136096
Pays : United States
Informations de copyright
© 2022 The Authors.
Références
Cell. 2017 Jul 27;170(3):507-521.e18
pubmed: 28735753
J Biol Chem. 1998 Dec 11;273(50):33660-6
pubmed: 9837951
Sci Adv. 2020 Sep 18;6(38):
pubmed: 32948589
Elife. 2021 Jun 28;10:
pubmed: 34180392
Nat Commun. 2013;4:1908
pubmed: 23715267
Mol Cell. 2003 Jan;11(1):203-13
pubmed: 12535533
Nucleic Acids Res. 2007;35(11):3810-22
pubmed: 17526531
Genome Biol. 2016 Aug 31;17(1):182
pubmed: 27582050
Biochemistry. 2021 Jun 1;60(21):1630-1641
pubmed: 34008964
Genes (Basel). 2016 Dec 21;7(12):
pubmed: 28009828
Nat Cell Biol. 2017 May;19(5):468-479
pubmed: 28368371
Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):E4565-70
pubmed: 26240319
Genes Dev. 2019 Nov 1;33(21-22):1539-1554
pubmed: 31624083
Nucleic Acids Res. 2013 Aug;41(15):7313-31
pubmed: 23757188
EMBO J. 2001 Nov 15;20(22):6509-19
pubmed: 11707421
Mol Pharmacol. 1998 Jul;54(1):78-85
pubmed: 9658192
Genes (Basel). 2016 Jul 01;7(7):
pubmed: 27376333
Mutat Res. 2015 Mar;773:9-15
pubmed: 25705119
Mol Cell. 2019 Mar 7;73(5):915-929.e6
pubmed: 30849395
Cancer Res. 1987 Apr 15;47(8):2050-5
pubmed: 3030540
Cancer Res. 1989 Nov 15;49(22):6365-8
pubmed: 2553254
Int J Mol Sci. 2018 Sep 14;19(9):
pubmed: 30223465
Mol Cell. 2017 Jan 5;65(1):117-130
pubmed: 27989438
Cell Rep. 2020 Jun 2;31(9):107705
pubmed: 32492421
Curr Biol. 2014 Jul 7;24(13):1467-1475
pubmed: 24954049
Mol Cell. 2019 Jul 25;75(2):252-266.e8
pubmed: 31202577
Life Sci Alliance. 2019 Apr 12;2(2):
pubmed: 30979826
Mol Cell. 2002 Mar;9(3):515-25
pubmed: 11931760
Cell. 2019 Oct 17;179(3):619-631.e15
pubmed: 31626768
Genetics. 2016 Jul;203(3):1027-67
pubmed: 27384026
Nature. 2015 Sep 17;525(7569):345-50
pubmed: 26322582
Nat Rev Mol Cell Biol. 2020 Oct;21(10):633-651
pubmed: 32612242
Mol Cell. 2000 Apr;5(4):617-27
pubmed: 10882098
Nat Rev Cancer. 2009 May;9(5):338-50
pubmed: 19377506
Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9053-8
pubmed: 18574145
Mol Pharmacol. 1992 Jun;41(6):993-8
pubmed: 1614415
PLoS One. 2013 Nov 07;8(11):e79202
pubmed: 24244448
Nature. 2007 Jul 12;448(7150):213-7
pubmed: 17589503
Nucleic Acids Res. 1990 Nov 25;18(22):6611-9
pubmed: 2174543
Proc Natl Acad Sci U S A. 2020 Jun 30;117(26):15182-15192
pubmed: 32554494
Cell Rep. 2019 Oct 8;29(2):422-436.e5
pubmed: 31597101
Mol Cell Biol. 2000 Jun;20(11):3977-87
pubmed: 10805740
Mol Pharmacol. 2019 Oct;96(4):475-484
pubmed: 31399497
Mol Cell. 2021 Mar 18;81(6):1309-1318.e6
pubmed: 33484638
Nucleic Acids Res. 2008 Sep;36(16):e100
pubmed: 18632763
Nucleic Acids Res. 2009 Apr;37(7):2238-48
pubmed: 19237397
Nature. 2019 Mar;567(7747):267-272
pubmed: 30842657
Cancer Res. 1989 Sep 15;49(18):5077-82
pubmed: 2548710
EMBO J. 2022 Jun 14;41(12):e110632
pubmed: 35578785
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4053-4060
pubmed: 32041867
Cell. 2014 Oct 9;159(2):346-57
pubmed: 25303529
Biochemistry. 1990 Jan 16;29(2):562-9
pubmed: 2154250
Mol Cell. 1998 Mar;1(4):519-29
pubmed: 9660936
Pharmacol Ther. 2017 Dec;180:16-23
pubmed: 28579387
Blood. 2001 May 1;97(9):2839-45
pubmed: 11313279
Biochim Biophys Acta. 2016 Jun;1860(6):1129-38
pubmed: 26922833
Genes Dev. 2017 Feb 1;31(3):275-290
pubmed: 28235849
Mol Cell. 2011 Oct 7;44(1):97-107
pubmed: 21981921
PLoS One. 2009 Jun 10;4(6):e5859
pubmed: 19516899
Cancer Res. 1985 Jul;45(7):3106-12
pubmed: 3839166
Mol Cell. 2020 May 21;78(4):739-751.e8
pubmed: 32259483
Cell. 1977 Feb;10(2):237-43
pubmed: 189936
Curr Biol. 2013 May 6;23(9):782-7
pubmed: 23602475
Int J Clin Oncol. 2017 Aug;22(4):619-628
pubmed: 28643177
Biochim Biophys Acta. 2014 Jan;1845(1):84-9
pubmed: 24361676
J Cell Biol. 2015 Mar 2;208(5):563-79
pubmed: 25733714
Biochemistry. 1991 Feb 19;30(7):1807-13
pubmed: 1847075
Methods Mol Biol. 2009;521:229-52
pubmed: 19563110
Cell. 2020 Jul 23;182(2):481-496.e21
pubmed: 32649862
DNA Repair (Amst). 2020 Oct;94:102926
pubmed: 32674013
DNA Repair (Amst). 2008 Mar 1;7(3):452-63
pubmed: 18206427
Mol Cell. 2010 Feb 26;37(4):492-502
pubmed: 20188668
Nat Rev Mol Cell Biol. 2016 Nov;17(11):703-721
pubmed: 27649880