Mechanisms of oncogenic chromosomal translocations

Michael Byrne, Justin Wray, Brian Reinert, Yuehan Wu, Jac Nickoloff, Suk Hee Lee, Robert Hromas, Elizabeth Williamson

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Chromosome translocations are caused by inappropriate religation of two DNA double-strand breaks (DSBs) in heterologous chromosomes. These DSBs can be generated by endogenous or exogenous sources. Endogenous sources of DSBs leading to translocations include inappropriate recombination activating gene (RAG) or activation-induced deaminase (AID) activity during immune receptor maturation. Endogenous DSBs can also occur at noncanonical DNA structures or at collapsed replication forks. Exogenous sources of DSBs leading to translocations include ionizing radiation (IR) and cancer chemotherapy. Spatial proximity of the heterologous chromosomes is also important for translocations. While three distinct pathways for DNA DSB repair exist, mounting evidence supports alternative nonhomologous end joining (aNHEJ) as the predominant pathway through which the majority of translocations occur. Initiated by poly (ADP-ribose) polymerase 1 (PARP1), aNHEJ is utilized less frequently in DNA DSB repair than other forms of DSB repair. We recently found that PARP1 is essential for chromosomal translocations to occur and that small molecule PARP1 inhibitors, already in clinical use, can inhibit translocations generated by IR or topoisomerase II inhibition. These data confirm the central role of PARP1 in aNHEJ-mediated chromosomal translocations and raise the possibility of using clinically available PARP1 inhibitors in patients who are at high risk for secondary oncogenic chromosomal translocations.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalAnnals of the New York Academy of Sciences
Volume1310
Issue number1
DOIs
StatePublished - Mar 2014
Externally publishedYes

Keywords

  • Chromosomal translocation
  • DNA end-joining repair
  • DNA repair
  • Oncogenesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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