Backup Pathways of Nonhomologous End Joining May Have a Dominant Role in the Formation of Chromosome Aberrations

Abstract

Chromosome aberrations are large-scale chromatin rearrangements produced in cells after exposure to ionizing radiation and other DNA-damaging agents. They have been directly implicated in cell killing, mutation induction and oncogenic transformation and have spearheaded a great number of investigations focused on their qualitative and quantitative analysis. The central aim of modern cytogenetics is the description at the molecular level of the observations at the chromosome level. There is consensus that the majority of chromosome aberrations are the ultimate consequence of errors in the repair of DNA double-strand breaks (DSBs). Here, we outline the molecular aspects of DSB repair pathways and discuss them vis-à-vis the two prominent theories of chromosome aberration formation. Although both homologydependent and homology-independent pathways contribute to DSB repair, homology-independent pathways are predominantly responsible for the initial removal of the majority of DSBs from the genome. From the homologyindependent pathways, both DNA-PK-dependent nonhomologous end joining (D-NHEJ) and backup nonhomologous end joining (B-NHEJ) have the potential of forming chromosome aberrations, but it is likely that most of the aberrations derive from a combination of low-frequency misjoining events during D-NHEJ, and from much higher frequency misjoining events during B-NHEJ. Further elucidation of the mechanism of DSB repair at the level of chromatin will allow a more complete molecular description of the process.