Deletions associated with stabilization of the Top1 cleavage complex in yeast are products of the nonhomologous end-joining pathway.

Published

Journal Article

Topoisomerase I (Top1) resolves supercoils by nicking one DNA strand and facilitating religation after torsional stress has been relieved. During its reaction cycle, Top1 forms a covalent cleavage complex (Top1cc) with the nicked DNA, and this intermediate can be converted into a toxic double-strand break (DSB) during DNA replication. We previously reported that Top1cc trapping in yeast increases DSB-independent, short deletions at tandemly repeated sequences. In the current study, we report a type of DSB-dependent mutation associated with Top1cc stabilization: large deletions (median size, ∼100 bp) with little or no homology at deletion junctions. Genetic analyses demonstrated that Top1cc-dependent large deletions are products of the nonhomologous end-joining (NHEJ) pathway and require Top1cc removal from DNA ends. Furthermore, these events accumulated in quiescent cells, suggesting that the causative DSBs may arise outside the context of replication. We propose a model in which the ends of different, Top1-associated DSBs are joined via NHEJ, which results in deletion of the intervening sequence. These findings have important implications for understanding the mutagenic effects of chemotherapeutic drugs that stabilize the Top1cc.

Full Text

Duke Authors

Cited Authors

  • Cho, J-E; Jinks-Robertson, S

Published Date

  • November 5, 2019

Published In

Volume / Issue

  • 116 / 45

Start / End Page

  • 22683 - 22691

PubMed ID

  • 31636207

Pubmed Central ID

  • 31636207

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1914081116

Language

  • eng

Conference Location

  • United States