02 May 2003
Camptothecin induced topoisomerase I-DNA complexes are targeted and reversed by poly(ADP-ribose)
M. Malanga, O. Cohausz, F. AlthausMed Sci Monit 2003; 9(1): 38-0 :: ID: 15101
Abstract
Camptothecin (CPT) and its clinically used congeners base their potency as anticancer drugs on the ability to stabilize topoisomerase I-cleaved DNA covalent complexes; such long-lived nucleoprotein complexes constitute a challenge to genomic integrity and cell viability as they can be converted in potentially lethal DNA damage upon collision with replication/transcription machineries [1]. Many DNA structural lesions have been shown to have a similar ‘poisoning’ effect [2]. The observation that PARP inhibitors potentiate the cytotoxicity of CPT in irradiated cells [3] suggests a correlation between poly(ADP-ribose) synthesis and cell’s ability to cope with topoisomerase I-induced DNA damage. Using an in vitro system we investigated whether the steady state level of topoisomerase I-DNA complexes could be modulated by poly(ADP-ribosyl)ation. We observed that both PARP-1 and PARP-2 in their automodified form reduced topoisomerase I-DNA covalent complexes, while they had little or no effect in their native state. The decrease in the number of nucleoprotein complexes occurred even in the presence of CPT and appeared to be specifically dependent on, and proportional to, the amount of PARP-bound poly(ADP-ribose). We found that poly(ADP-ribose) interacts noncovalently with topoisomerase I and identified two binding motifs at critical sites for the enzyme activity. Further experiments revealed that topoisomerase I in covalent complex with its substrate was a preferred target for poly(ADP-ribose). Such specific targeting resulted in a complete reversion of the cleavage complexes, in spite of the stabilizing effect of CPT. Work is in progress to evaluate the occurrence of such poly(ADP-ribose)-mediated repair of topoisomerase I-DNA covalent complexes in living cells. References: 1.Kohn KW, Pommier Y: Annals NY Acad Sci, 2000; 922: 11-26 2.Pourquier P, Waltman JL, Urasaki Y et al: Cancer Res, 2001; 61: 53-58 3.Bowman KJ, Newell DR, Calvert AH, Curtin NJ: Br J Cancer, 2001; 84: 106-112
Keywords: PARP-2, noncovalent interactions, DNA Repair
Editorial
01 April 2025 : Editorial
Editorial: Rapid Testing for the Avian Influenza A(H5N1) Virus is Urgently Required as Infections in Poultry and Dairy Cows are on the Rise, and so is Transmission to HumansDOI: 10.12659/MSM.949109
Med Sci Monit 2025; 31:e949109
In Press
Clinical Research
Buccal Acupuncture Reduces the Dose of Sufentanil Needed in Laparoscopic Gynecological SurgeryMed Sci Monit In Press; DOI: 10.12659/MSM.947088
Review article
Global Guidelines and Trends in HPV Vaccination for Cervical Cancer PreventionMed Sci Monit In Press; DOI: 10.12659/MSM.947173
Clinical Research
Serum Prolidase and Ischemia-Modified Albumin Levels in Neural Tube Defects: A Comparative Study of Myelome...Med Sci Monit In Press; DOI: 10.12659/MSM.947873
Clinical Research
Impact of Depression, Fatigue, and Pain on Quality of Life in Slovak Multiple Sclerosis PatientsMed Sci Monit In Press; DOI: 10.12659/MSM.947630
Most Viewed Current Articles
17 Jan 2024 : Review article 7,932,897
Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron VariantDOI :10.12659/MSM.942799
Med Sci Monit 2024; 30:e942799
16 May 2023 : Clinical Research 702,919
Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...DOI :10.12659/MSM.940387
Med Sci Monit 2023; 29:e940387
01 Mar 2024 : Editorial 29,882
Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and ...DOI :10.12659/MSM.944204
Med Sci Monit 2024; 30:e944204
28 Jan 2024 : Review article 23,844
A Review of IgA Vasculitis (Henoch-Schönlein Purpura) Past, Present, and FutureDOI :10.12659/MSM.943912
Med Sci Monit 2024; 30:e943912