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Whole genome sequencing of cancer genomes has revealed a diversity of recurrent gross chromosomal rearrangements (GCRs) that are likely signatures of specific defects in DNA damage response pathways. However, inferring the underlying defects has been difficult due to insufficient information relating defects in DNA metabolism to GCR signatures. By analyzing over 95 mutant strains of  Saccharomyces cerevisiae , we found that the frequency of GCRs that deleted an internal  CAN1/URA3  cassette on chrV L while retaining a chrV L telomeric  hph  marker was significantly higher in  tel1Δ ,  sae2Δ ,  rad53Δ sml1Δ , and  mrc1Δ tof1Δ  mutants. The  hph -retaining GCRs isolated from  tel1Δ  mutants contained either an interstitial deletion dependent on non-homologous end-joining or an inverted duplication that appeared to be initiated from a double strand break (DSB) on chrV L followed by hairpin formation, copying of chrV L from the DSB toward the centromere, and homologous recombination to capture the  hph -containing end of chrV L. In contrast,  hph -containing GCRs from other mutants were primarily interstitial deletions ( mrc1Δ tof1Δ ) or inverted duplications ( sae2Δ  and  rad53Δ sml1Δ ). Mutants with impaired  de novo  telomere addition had increased frequencies of  hph -containing GCRs, whereas mutants with increased  de novo  telomere addition had decreased frequencies of  hph -containing GCRs. Both types of  hph -retaining GCRs occurred in wild-type strains, suggesting that the increased frequencies of  hph  retention were due to the relative efficiencies of competing DNA repair pathways. Interestingly, the inverted duplications observed here resemble common GCRs in metastatic pancreatic cancer.

DNA Repair Pathway Selection Caused by Defects in TEL1, SAE2, and De Novo Telomere Addition Generates Specific Chromosomal Rearrangement Signatures