Methylated DNA causes a physical block to replication forks independently of damage signalling, O(6)-methylguanine or DNA single-strand breaks and results in DNA damage.

Journal of Molecular Biology
Petra GrothThomas Helleday

Abstract

Even though DNA alkylating agents have been used for many decades in the treatment of cancer, it remains unclear what happens when replication forks encounter alkylated DNA. Here, we used the DNA fibre assay to study the impact of alkylating agents on replication fork progression. We found that the alkylator methyl methanesulfonate (MMS) inhibits replication elongation in a manner that is dose dependent and related to the overall alkylation grade. Replication forks seem to be completely blocked as no nucleotide incorporation can be detected following 1 h of MMS treatment. A high dose of 5 mM caffeine, inhibiting most DNA damage signalling, decreases replication rates overall but does not reverse MMS-induced replication inhibition, showing that the replication block is independent of DNA damage signalling. Furthermore, the block of replication fork progression does not correlate with the level of DNA single-strand breaks. Overexpression of O(6)-methylguanine (O6meG)-DNA methyltransferase protein, responsible for removing the most toxic alkylation, O6meG, did not affect replication elongation following exposure to N-methyl-N'-nitro-N-nitrosoguanidine. This demonstrates that O6meG lesions are efficiently bypassed in mammalian cell...Continue Reading

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Citations

Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Muralidhar L HegdeSankar Mitra
Jun 8, 2011·Nucleic Acids Research·Ingegerd ElversThomas Helleday
Jan 6, 2016·The Journal of Clinical Investigation·Ryan M NaylorJan M van Deursen
Dec 27, 2011·Pharmacology & Therapeutics·K AzizA G Georgakilas
Mar 24, 2016·Nucleic Acids Research·Ryan JankeWolf-Dietrich Heyer
Jul 2, 2014·The Journal of Cell Biology·Michael EnsmingerMarkus Lӧbrich
Apr 29, 2014·DNA Repair·Jun NakamuraJames Swenberg
Aug 14, 2012·Molecular Cell·Mireille Tittel-ElmerJennifer A Cobb
Sep 4, 2016·FEMS Yeast Research·Julieta Martino, Kara A Bernstein
Jun 7, 2019·The Journal of Biological Chemistry·Hua DuYinsheng Wang
Oct 12, 2018·Nucleic Acids Research·Ann-Sofie JemthThomas Helleday
Feb 23, 2020·Cancer Biotherapy & Radiopharmaceuticals·Dankai ZhanJianguang Jia
Apr 21, 2017·Oncotarget·Anna HagenkortThomas Helleday
Sep 29, 2019·Nature Communications·Jennifer M MasonDouglas K Bishop
Sep 27, 2018·Nature Communications·Nina M S GustafssonThomas Helleday
Jan 19, 2019·International Journal of Molecular Sciences·Bayan Bokhari, Sudha Sharma
Nov 16, 2018·Proceedings of the National Academy of Sciences of the United States of America·Kun YangMarc M Greenberg
Oct 29, 2015·The FEBS Journal·Jordi Carreras PuigvertThomas Helleday
Nov 27, 2020·The Biochemical Journal·Shephali BansodSunanda Bhattacharyya
Feb 19, 2021·Matrix Biology : Journal of the International Society for Matrix Biology·Thomas Juretschke, Petra Beli
Oct 6, 2021·Archives of Toxicology·Ezgi Eyluel BankogluHelga Stopper

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