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

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 tel1, sae2, rad53 sml1, and mrc1 tof1 mutants. The hph-retaining GCRs isolated from tel1 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 (mrc1 tof1) or inverted duplications (sae2 and rad53 sml1). 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. Author Summary Recent advances in the sequencing of human cancer genomes have revealed that some types of genome rearrangements are more common in specific types of cancers. Thus, these cancers may share defects in DNA repair mechanisms, which may play roles in initiation or progression of the disease and may be useful therapeutically. Linking a common rearrangement signature to a specific genetic or epigenetic alteration is currently challenging, because we do not know which rearrangement signatures are linked to which DNA repair defects. Here we used a genetic assay in the model organism Saccharomyces cerevisiae to specifically link two classes of chromosomal rearrangements, interstitial deletions and inverted duplications, to specific genetic defects. These results begin to map out the links between observed chromosomal rearrangements and specific DNA repair defects and in the present case, may provide insights into the chromosomal rearrangements frequently observed in metastatic pancreatic cancer.