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

Ensminger, Michael and Iloff, Lucie and Ebel, Christian and Nikolova, Teodora and Kaina, Bernd and Löbrich, Markus :
DNA breaks and chromosomal aberrations arise when replication meets base excision repair.
In: The Journal of cell biology, 206 (1) pp. 29-43. ISSN 1540-8140
[Article] , (2014)

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.

Item Type: Article
Erschienen: 2014
Creators: Ensminger, Michael and Iloff, Lucie and Ebel, Christian and Nikolova, Teodora and Kaina, Bernd and Löbrich, Markus
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: The Journal of cell biology
Volume: 206
Number: 1
Divisions: 10 Department of Biology
10 Department of Biology > Radiation Biology and DNA Repair
Date Deposited: 11 Sep 2014 08:22
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