Genome-Protective Topoisomerase 2a-Dependent G2 Arrest Requires p53 in hTERT-Positive Cancer Cells.
Journal
Cancer research
ISSN: 1538-7445
Titre abrégé: Cancer Res
Pays: United States
ID NLM: 2984705R
Informations de publication
Date de publication:
03 05 2022
03 05 2022
Historique:
received:
03
06
2021
revised:
01
02
2022
accepted:
25
02
2022
pubmed:
6
3
2022
medline:
4
5
2022
entrez:
5
3
2022
Statut:
ppublish
Résumé
Topoisomerase 2a (Topo2a)-dependent G2 arrest engenders faithful segregation of sister chromatids, yet in certain tumor cell lines where this arrest is dysfunctional, a PKCε-dependent failsafe pathway can be triggered. Here we elaborate on recent advances in understanding the underlying mechanisms associated with this G2 arrest by determining that p53-p21 signaling is essential for efficient arrest in cell lines, in patient-derived cells, and in colorectal cancer organoids. Regulation of this p53 axis required the SMC5/6 complex, which is distinct from the p53 pathways observed in the DNA damage response. Topo2a inhibition specifically during S phase did not trigger G2 arrest despite affecting completion of DNA replication. Moreover, in cancer cells reliant upon the alternative lengthening of telomeres (ALT) mechanism, a distinct form of Topo2a-dependent, p53-independent G2 arrest was found to be mediated by BLM and Chk1. Importantly, the previously described PKCε-dependent mitotic failsafe was engaged in hTERT-positive cells when Topo2a-dependent G2 arrest was dysfunctional and where p53 was absent, but not in cells dependent on the ALT mechanism. In PKCε knockout mice, p53 deletion elicited tumors were less aggressive than in PKCε-replete animals and exhibited a distinct pattern of chromosomal rearrangements. This evidence suggests the potential of exploiting synthetic lethality in arrest-defective hTERT-positive tumors through PKCε-directed therapeutic intervention. The identification of a requirement for p53 in stringent Topo2a-dependent G2 arrest and engagement of PKCε failsafe pathways in arrest-defective hTERT-positive cells provides a therapeutic opportunity to induce selective synthetic lethality.
Identifiants
pubmed: 35247890
pii: 681975
doi: 10.1158/0008-5472.CAN-21-1785
pmc: PMC7612711
mid: EMS144799
doi:
Substances chimiques
Poly-ADP-Ribose Binding Proteins
0
Tumor Suppressor Protein p53
0
DNA Topoisomerases, Type II
EC 5.99.1.3
TOP2A protein, human
EC 5.99.1.3
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1762-1773Subventions
Organisme : Medical Research Council
ID : FC001130
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001130
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001130
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210752/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001130
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001130
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 210752
Pays : United Kingdom
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
Nat Cell Biol. 2019 Apr;21(4):487-497
pubmed: 30804506
Oncogene. 2011 Oct 13;30(41):4261-74
pubmed: 21532626
J Mol Cell Biol. 2019 Apr 1;11(4):293-305
pubmed: 30508182
Clin Cancer Res. 2012 Oct 15;18(20):5650-61
pubmed: 22929806
Cell Rep. 2019 Oct 8;29(2):422-436.e5
pubmed: 31597101
EMBO J. 1999 Apr 1;18(7):1815-23
pubmed: 10202145
Blood Cancer J. 2020 Apr 28;10(4):45
pubmed: 32345961
Adv Biol Regul. 2020 Dec;78:100759
pubmed: 33039823
Cell Cycle. 2007 May 15;6(10):1265-7
pubmed: 17495539
Cell. 2010 Jul 23;142(2):230-42
pubmed: 20655466
Cell Mol Life Sci. 2015 May;72(9):1825-37
pubmed: 25430478
Genes Dev. 2021 Aug 1;35(15-16):1093-1108
pubmed: 34266887
Nat Struct Mol Biol. 2007 Jul;14(7):581-90
pubmed: 17589526
Mol Cell. 2019 Oct 3;76(1):27-43.e11
pubmed: 31447390
Nucleic Acids Res. 2013 Aug;41(15):7313-31
pubmed: 23757188
Nucleic Acids Res. 2019 Apr 8;47(6):2906-2921
pubmed: 30590722
Cell. 2007 Jan 12;128(1):101-14
pubmed: 17218258
Exp Cell Res. 2006 Jul 1;312(11):1996-2008
pubmed: 16630610
Am J Physiol Cell Physiol. 2015 Mar 1;308(5):C372-7
pubmed: 25518961
Nat Commun. 2014 Dec 08;5:5685
pubmed: 25483024
Nature. 1994 Dec 1;372(6505):467-70
pubmed: 7984241
Cancer Res. 2011 Jan 15;71(2):463-72
pubmed: 21239475
Cold Spring Harb Symp Quant Biol. 2017;82:187-195
pubmed: 29167280
Nat Commun. 2018 Feb 14;9(1):677
pubmed: 29445165
Oncogene. 1999 Dec 13;18(53):7644-55
pubmed: 10618704
Oncogene. 1999 Jul 8;18(27):3989-95
pubmed: 10435622
Elife. 2017 Mar 20;6:
pubmed: 28318489
Science. 1998 Sep 11;281(5383):1674-7
pubmed: 9733514
Genes Dev. 2000 Jun 15;14(12):1448-59
pubmed: 10859164
Annu Rev Med. 2015;66:455-70
pubmed: 25341009
Cell Cycle. 2002 May-Jun;1(3):210-9
pubmed: 12429935
Trends Cancer. 2015 Oct 1;1(2):145-156
pubmed: 26645051
Mol Cell. 2008 Jun 20;30(6):790-802
pubmed: 18570880
Genome Res. 2014 Dec;24(12):2022-32
pubmed: 25236618
Nat Cell Biol. 2009 Jun;11(6):753-60
pubmed: 19465922
Nat Rev Mol Cell Biol. 2010 Mar;11(3):208-19
pubmed: 20177396
J Biol Chem. 2009 May 29;284(22):14966-77
pubmed: 19329795
Cell. 2015 May 7;161(4):933-45
pubmed: 25957691
Cell Cycle. 2009 Jan 15;8(2):253-6
pubmed: 19158493
Mol Carcinog. 1995 Sep;14(1):16-22
pubmed: 7546219
Hum Mutat. 2016 Sep;37(9):865-76
pubmed: 27328919
J Cell Biol. 2013 May 13;201(4):511-21
pubmed: 23649806
Nat Struct Mol Biol. 2005 Jul;12(7):589-93
pubmed: 15965487
Science. 2000 Mar 10;287(5459):1824-7
pubmed: 10710310
Cancer Res. 2011 Jan 15;71(2):561-71
pubmed: 21224348
Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10389-94
pubmed: 10973490
EMBO J. 2003 Aug 1;22(15):3992-4002
pubmed: 12881433
J Clin Invest. 2014 Sep;124(9):4028-38
pubmed: 25105364
Cell Cycle. 2009 Oct 1;8(19):3065-6
pubmed: 19755843