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

Fernando Gómez-Herreros

doi:10.3389/fmolb.2019.00141

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.

Highlights

Chromosomal translocations are rearrangements of large fragments of DNA
Recurrence of chromosomal translocations is determined by a large number of factors, starting from the nature of the DNA break and including the pathway involved in its repair, the cell cycle stage, the chromatin status of the locus, and the genomic location of the lesion
In contrast to homologous recombination (HR), non-homologous end joining (NHEJ) is active throughout the cell cycle and involves the efficient ligation of DNA ends with minimal processing at the site of joining

Summary

Introduction

Chromosomal translocations are rearrangements of large fragments of DNA. When transcribed regions are affected, genome translocations usually result in the inactivation of one or a group of genes with the consequent deleterious effects for cellular survival. Recurrence of chromosomal translocations is determined by a large number of factors, starting from the nature of the DNA break and including the pathway involved in its repair, the cell cycle stage, the chromatin status of the locus, and the genomic location of the lesion. TOP2-Induced Chromosomal Translocations of DNA double-stranded breaks (DSBs) and they promote chromosomal translocations.

Results

Conclusion