Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations.
Chromosome translocations are frequently associated with many types of blood-related cancers and childhood sarcomas. Detection of chromosome translocations assists in diagnosis, treatment and prognosis of these diseases; however, despite their importance to such diseases, the molecular mechanisms leading to chromosome translocations are not well understood. The available evidence indicates a role for non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) in their origin. Here we develop a yeast-based system that induces a reciprocal chromosome translocation by formation and ligation of breaks on two different chromosomes. We show that interchromosomal end joining is efficiently suppressed by the Tel1- and Mre11-Rad50-Xrs2-dependent pathway; this is distinct from the role of Tel1 in telomeric integrity and from Mec1- and Tel1-dependent checkpoint controls. Suppression of DSB-induced chromosome translocations depends on the kinase activity of Tel1 and Dun1, and the damage-induced phosphorylation of Sae2 and histone H2AX proteins. Tel1- and Sae2-dependent tethering and promotion of 5' to 3' degradation of broken chromosome ends discourage error-prone NHEJ and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Our results indicate that, like human ATM, Tel1 serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.
Lee
Kihoon
K
Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA.
Zhang
Yu
Y
Lee
Sang Eun
SE
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D019457:Chromosome Breakage; D015825:Chromosomes, Fungal / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D004706:Endodeoxyribonucleases / Q000378:metabolism; D004720:Endonucleases; D005090:Exodeoxyribonucleases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014178:Translocation, Genetic; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C086930:RAD50 protein, S cerevisiae; C107849:SAE2 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D025521:Tumor Suppressor Proteins; C086929:XRS2 protein, S cerevisiae; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D004706:Endodeoxyribonucleases; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae