DNA Double Strand Breaks and Chromosomal Translocations Induced by DNA Topoisomerase II

Abstract

DNA double strand breaks (DSBs) are the most cytotoxic lesions of those occurring in the DNA and can lead to cell death or result in genome mutagenesis and chromosomal translocations. Although most of these rearrangements have detrimental effects for cellular survival, single events can provide clonal advantage and result in abnormal cellular proliferation and cancer. The origin and the environment of the DNA break or the repair pathway are key factors that influence the frequency at which these events appear. However, the molecular mechanisms that underlie the formation of chromosomal translocations remain unclear. DNA topoisomerases are essential enzymes present in all cellular organisms with critical roles in DNA metabolism and that have been linked to the formation of deleterious DSBs for a long time. DSBs induced by the abortive activity of DNA topoisomerase II (TOP2) are "trending topic" because of their possible role in genome instability and oncogenesis. Furthermore, transcription associated TOP2 activity appears to be one of the most determining causes behind the formation of chromosomal translocations. In this review, the origin of recombinogenic TOP2 breaks and the determinants behind their tendency to translocate will be summarized.

Canonical non-homologous end-joining promotes genome mutagenesis and translocations induced by transcription-associated DNA topoisomerase 2 activity

“…For example, these may be related to spatial organisation of the genome, since recent studies have shown that loop anchors, bound by CTCF and cohesin, can mediate TOP2ß abortive breaks ( 9 , 42 , 43 ). To what extent this activity accounts for transcription-induced DSBs remains controversial ( 14 ).…”

“…The remaining peptide can be then removed via the nuclease activity of the MRN complex ( 11 ) or by tyrosyl-DNA phosphodiesterase 2 (TDP2) ( 12 , 13 ). TDP2 cleaves the phosphotyrosyl bond between the topoisomerase peptide and the 5′ phosphate of the DNA, generating error-free ligatable ends that can be processed by the non-homologous end-joining (NHEJ) pathway ( 14 , 15 ).…”

“…Homologous recombination (HR) is largely an error-free DNA pathway that prevents genome instability during S and G2 phases of the cell cycle ( 14 ). In contrast, NHEJ is a rapid and efficient repair pathway that is active throughout the cell cycle, but can be considered error-prone as, under some circumstances, nucleases may modify the DNA to make it compatible for ligation.…”

“…Whereas studies in mice lymphoblasts demonstrated that cNHEJ prevents genomic translocations that are mediated by altNHEJ ( 16 ), recent studies in human cells have shown that ionizing radiation and nuclease-induced translocations are dependent on cNHEJ ( 22–24 ). In the case of TOP2-induced translocations, this question remains unresolved ( 14 ).…”

Recent Perspectives in Radiation-Mediated DNA Damage and Repair: Role of NHEJ and Alternative Pathways

“…In addition, adjacent single-strand breaks in opposite strands may be converted to double strand breaks upon replication. DSBs are lethal unless repaired [27]. Ionizing radiations also induce clustered DNA damage in cells, which symbolize two, or more lesions formed within one or two helical turns of DNA and are in part responsible for the biological effects of ionizing radiation.…”