DNA replication initiation shapes the mutational landscape and expression of the human genome (ATAC-Seq)

The interplay between active biological processes and DNA repair is central to mutagenesis. We found that the ubiquitous process of replication initiation is mutagenic, leaving a specific mutational footprint at thousands of early and efficient replication origins. The observed mutational pattern is consistent with the formation of DNA breaks at the centre of the origins and local error-prone DNA synthesis in their immediate vicinity. To support our mutational signature analysis, we performed DSBs mapping (INDUCE-seq) in parallel with RNA-seq, ATAC-seq and TOP2A/B CUT&RUN assays and show that origin activation leads to the TOP2A/B-dependent accumulation of DSBs at origins found at TSS and splice sites of both expressed and non-expressed genes in human H9 embryonic stem cells. Overall design: ATAC-seq analysis of H9 cells.