Induction of genome instability by DNA damage in Saccharomyces cerevisiae.
The accumulation of gross chromosomal rearrangements (GCRs) is a characteristic of many types of cancer cells, although it is unclear what defects cause these rearrangements and how the different types of GCRs observed are formed. In the present study, we have used a Saccharomyces cerevisiae system for measuring GCRs to analyze the ability of a variety of DNA damaging agents to induce GCRs. The two most potent inducers of GCRs observed were methyl methane sulfonate (MMS) and HO-endonuclease-induced double strand breaks (DSBs). Bleomycin, camptothecan and gamma-irradiation induced intermediate levels of GCRs and cisplatin induced very low levels of GCRs whereas N-methyl-NPRIME;-nitro-N-nitrosoguanidine (MNNG) and ethyl methane sulfonate (EMS) primarily induced base substitution mutations. MMS treatment primarily induced rearrangements in which the end of a chromosome was deleted and a new telomere was added (telomere additions) and also induced translocations. Consistent with this GCR spectrum, the formation of MMS-induced GCRs was primarily dependent on telomere maintenance functions and were completely eliminated in mutants that were defective for both telomere maintenance functions and non-homologous end joining (NHEJ). In contrast, HO-endonuclease DSBs induced mostly translocations and interstitial deletions whereas few telomere additions were observed. Genetic analysis indicated that HO DSB-induced GCRs were suppressed by a number of pathways including the DNA damage checkpoints, DSB repair pathways and NHEJ.
Myung
Kyungjae
K
Department of Medicine, School of Medicine, University of California at San Diego, CMME3058, 9500 Gilman Drive, La Jolla, CA 92093-0669, USA.
Kolodner
Richard D
RD
D002869:Chromosome Aberrations / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D015252:Deoxyribonucleases, Type II Site-Specific / Q000494:pharmacology; D016681:Genome, Fungal; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase / Q000378:metabolism
D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D008741:Methyl Methanesulfonate; D019098:Telomerase; C530845:HO protein, S cerevisiae; C037725:SCEI protein, S cerevisiae; D015252:Deoxyribonucleases, Type II Site-Specific; D011088:DNA Ligases; D000072481:DNA Ligase ATP