title: DNA breaks and chromosomal aberrations arise when replication meets base excision repair.
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.
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Michael
authors: M
authors: Ensminger
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Lucie
authors: L
authors: Iloff
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Christian
authors: C
authors: Ebel
authors: Institute of Toxicology, Medical Center of the University Mainz, 55131 Mainz, Germany.
authors: Teodora
authors: T
authors: Nikolova
authors: Institute of Toxicology, Medical Center of the University Mainz, 55131 Mainz, Germany lobrich@bio.tu-darmstadt.de kaina@uni-mainz.de.
authors: Bernd
authors: B
authors: Kaina
authors: Radiation Biology and DNA Repair, Darmstadt University of Technology, 64287 Darmstadt, Germany.
authors: Markus
authors: M
authors: Lӧbrich
mesh_terms: D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D006224:Cricetinae; D003412:Cricetulus; D018736:DNA Adducts / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D045647:DNA Glycosylases / Q000378:metabolism; D019175:DNA Methylation; D004260:DNA Repair; D004261:DNA Replication; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice
chemical_list: D018736:DNA Adducts; C468783:H2AX protein, human; D006657:Histones; D045647:DNA Glycosylases