Suppression of gross chromosomal rearrangements by yKu70-yKu80 heterodimer through DNA damage checkpoints.
The inactivation of either subunit of the Ku70-Ku80 heterodimer, which functions in nonhomologous end-joining and telomere maintenance, generates severe defects such as sensitivity to DNA damage, telomere shortening, and increased gross chromosomal rearrangements (GCRs) that are frequently observed in many cancers. To understand the mechanism of Ku as a genome gatekeeper, we overexpressed the yKu70-yKu80 heterodimer and monitored the formation of GCRs. Ku overexpression suppressed the formation of either spontaneously generated GCRs or those induced by treatments with different DNA damaging agents. Interestingly, this suppression depended on Ku's interaction with DNA damage checkpoints and not through nonhomologous end-joining. We also demonstrate that the inactivation of telomerase inhibitor, Pif1 along with Ku overexpression or the overexpression of Pif1 in either yku70 or yku80 strains arrested the cell cycle at S phase in a DNA damage checkpoint-dependent fashion. Lastly, Ku overexpression causes cell growth delay, which depends on intact Rad27. In summary, the results presented here suggest that Ku functions as a genomic gatekeeper through its crosstalk with DNA damage checkpoints.
Banerjee
Soma
S
Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, 49 Convent Drive, Bethesda, MD 20892, USA.
Smith
Stephanie
S
Myung
Kyungjae
K
D034961:Antigens, Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D015825:Chromosomes, Fungal / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D045585:Flap Endonucleases / Q000235:genetics / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal; D000072200:Ku Autoantigen; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D034961:Antigens, Nuclear; D004268:DNA-Binding Proteins; D029701:Saccharomyces cerevisiae Proteins; D045585:Flap Endonucleases; C468323:RAD27 protein, S cerevisiae; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen