Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition

The cytotoxic effects of topoisomerase I inhibitors such as camptothecin can be modulated by replication fork reversal, in a process that requires Poly(ADP-ribose) polymerase (PARP) activity. Here human RECQ1 helicase is shown to restore such regressed replication forks, whereas PARP1 activity restr...

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Published in:Nature structural & molecular biology Vol. 20; no. 3; pp. 347 - 354
Main Authors: Berti, Matteo, Ray Chaudhuri, Arnab, Thangavel, Saravanabhavan, Gomathinayagam, Shivasankari, Kenig, Sasa, Vujanovic, Marko, Odreman, Federico, Glatter, Timo, Graziano, Simona, Mendoza-Maldonado, Ramiro, Marino, Francesca, Lucic, Bojana, Biasin, Valentina, Gstaiger, Matthias, Aebersold, Ruedi, Sidorova, Julia M, Monnat, Raymond J, Lopes, Massimo, Vindigni, Alessandro
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.03.2013
Nature Publishing Group
Subjects:
631/337/151
631/45/173
631/92/609
Adenosine diphosphate
Biochemistry
Biological Microscopy
Camptothecin - pharmacology
Cancer
Cell Line
Cytotoxicity
Deoxyribonucleic acid
DNA
DNA Replication
DNA Topoisomerases, Type I - metabolism
Enzymes
Gene expression
Genetic aspects
Humans
Inhibitor drugs
Inhibitors
Life Sciences
Membrane Biology
Molecular biology
Pharmacology
Physiological aspects
Poly (ADP-Ribose) Polymerase-1
Poly(ADP-ribose) Polymerases - genetics
Poly(ADP-ribose) Polymerases - metabolism
Protein Structure
RecQ Helicases - genetics
RecQ Helicases - metabolism
Structure
Topoisomerase I Inhibitors - pharmacology
Topoisomerases
United States
ISSN:1545-9993, 1545-9985, 1545-9985
Online Access:Get full text
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Summary:The cytotoxic effects of topoisomerase I inhibitors such as camptothecin can be modulated by replication fork reversal, in a process that requires Poly(ADP-ribose) polymerase (PARP) activity. Here human RECQ1 helicase is shown to restore such regressed replication forks, whereas PARP1 activity restrains this RECQ1 function. Topoisomerase I (TOP1) inhibitors are an important class of anticancer drugs. The cytotoxicity of TOP1 inhibitors can be modulated by replication fork reversal through a process that requires poly(ADP-ribose) polymerase (PARP) activity. Whether regressed forks can efficiently restart and what factors are required to restart fork progression after fork reversal are still unknown. We have combined biochemical and EM approaches with single-molecule DNA fiber analysis to identify a key role for human RECQ1 helicase in replication fork restart after TOP1 inhibition that is not shared by other human RecQ proteins. We show that the poly(ADP-ribosyl)ation activity of PARP1 stabilizes forks in the regressed state by limiting their restart by RECQ1. These studies provide new mechanistic insights into the roles of RECQ1 and PARP in DNA replication and offer molecular perspectives to potentiate chemotherapeutic regimens based on TOP1 inhibition.
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Current address: Proteomics Core Facility, Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
These two authors equally contributed to the work.
ISSN:1545-9993
1545-9985
1545-9985
DOI:10.1038/nsmb.2501