Telomere dysfunction increases mutation rate and genomic instability.
The increased tumor incidence in telomerase null mice suggests that telomere dysfunction induces genetic instability. To test this directly, we examined mutation rate in the absence of telomerase in S. cerevisiae. The mutation rate in the CAN1 gene increased 10- to 100-fold in est1Delta strains as telomeres became dysfunctional. This increased mutation rate resulted from an increased frequency of terminal deletions. Chromosome fusions were recovered from est1Delta strains, suggesting that the terminal deletions may occur by a breakage-fusion-bridge type mechanism. At one locus, chromosomes with terminal deletions gained a new telomere through a Rad52p-dependent, Rad51p-independent process consistent with break-induced replication. At a second locus, more complicated rearrangements involving multiple chromosomes were seen. These data suggest that telomerase can inhibit chromosomal instability.
Hackett
J A
JA
Predoctoral Training Program in Human Genetics and Molecular Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Feldser
D M
DM
Greider
C W
CW
D026905:Amino Acid Transport Systems; D001483:Base Sequence; D002262:Carboxy-Lyases / Q000235:genetics; D002869:Chromosome Aberrations / Q000235:genetics*; D019457:Chromosome Breakage / Q000235:genetics; D002872:Chromosome Deletion; D015825:Chromosomes, Fungal / Q000235:genetics / Q000378:metabolism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000378:metabolism; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005787:Gene Frequency; D020043:Genes, Essential / Q000235:genetics; D016681:Genome, Fungal; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000235:genetics; D016296:Mutagenesis / Q000235:genetics*; D051135:Rad51 Recombinase; D051721:Rad52 DNA Repair and Recombination Protein; D011995:Recombination, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics
D026905:Amino Acid Transport Systems; C097640:CAN1 protein, Candida albicans; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; C495151:RAD51 protein, S cerevisiae; D051135:Rad51 Recombinase; C099024:EST1 protein, S cerevisiae; D019098:Telomerase; D002262:Carboxy-Lyases; C022378:phosphoribosylaminoimidazole carboxylase; D011088:DNA Ligases; D000072481:DNA Ligase ATP