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DNA breaks and chromosomal aberrations arise when replication meets base excision repair

Ensminger, Michael ; Iloff, Lucie ; Ebel, Christian ; Nikolova, Teodora ; Kaina, Bernd ; Löbrich, Markus (2022):
DNA breaks and chromosomal aberrations arise when replication meets base excision repair. (Publisher's Version)
In: Journal of Cell Biology, 206 (1), pp. 29-43. Rockefeller University Press, ISSN 0021-9525, e-ISSN 1540-8140,
DOI: 10.26083/tuprints-00018940,
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Item Type: Article
Origin: Secondary publication service
Status: Publisher's Version
Title: DNA breaks and chromosomal aberrations arise when replication meets base excision repair
Language: English
Abstract:

Exposures that methylate DNA potently induce DNA double-strand breaks (DSBs) and chromosomal aberrations, which are thought to arise when damaged bases block DNA replication. Here, we demonstrate that DNA methylation damage causes DSB formation when replication interferes with base excision repair (BER), the predominant pathway for repairing methylated bases. We show that cells defective in the N-methylpurine DNA glycosylase, which fail to remove N-methylpurines from DNA and do not initiate BER, display strongly reduced levels of methylation-induced DSBs and chromosomal aberrations compared with wild-type cells. Also, cells unable to generate single-strand breaks (SSBs) at apurinic/apyrimidinic sites do not form DSBs immediately after methylation damage. In contrast, cells deficient in x-ray cross-complementing protein 1, DNA polymerase β, or poly (ADP-ribose) polymerase 1 activity, all of which fail to seal SSBs induced at apurinic/apyrimidinic sites, exhibit strongly elevated levels of methylation-induced DSBs and chromosomal aberrations. We propose that DSBs and chromosomal aberrations after treatment with N-alkylators arise when replication forks collide with SSBs generated during BER.

Journal or Publication Title: Journal of Cell Biology
Volume of the journal: 206
Issue Number: 1
Publisher: Rockefeller University Press
Classification DDC: 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
Divisions: 10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 11 Mar 2022 13:04
Last Modified: 11 Mar 2022 13:04
DOI: 10.26083/tuprints-00018940
Corresponding Links:
URN: urn:nbn:de:tuda-tuprints-189406
URI: https://tuprints.ulb.tu-darmstadt.de/id/eprint/18940
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