Role of transcription in DNA double strand break formation and repair processes

Abstract

Abnormal genome modifications, for example, translocations, accumulate if DNA-double-strand breaks (DSBs) are not repaired properly. Chromosomal translocations will be formed when part of a chromosome is transferred to a different part of the chromosome or to another chromosome. Since the location of long chromosome fragments are changed during the formation of translocations, chromosome translocations are thought to be the most severe form of genome aberration. In fact, in most of the cases, translocations usually have a tremendous impact, not only on the single cell, but also on the whole organism. It is found that translocations may cause aberrant transcription, cell death and even tumorigenesis. Recent work has identified several key factors in the formation of translocations including genomic spatial organization, chromatin structures and DSB repair pathways. However, the biogenesis of chromosome translocations especially in cancer genomes is still poorly understood. Here I analyzed cancer genomic data to show that chromosomal translocations are enriched in gene-coding regions, highlighting the potential interplay of transcription and DNA repair. Further analysis on structural variations among 10 cancer types showed that translocations preferentially accumulate at transcription start site (TSS) and transcription end site (TES) of non-silent genes. In addition, translocation distribution correlates with replication timing and homologous recombination deficiency (HRD). To investigate the impact of transcription on DNA repair, stable 293T cell lines with modified DSB repair reporters that allow inducible transcription were constructed. Together, our data points out that global transcription has an impact on DNA repair, which can contribute to chromosomal rearrangement. Moreover, cells may employ different mechanisms to coordinate DSB repair between global and local transcription.