DNA breaks disrupt the integrity of the chromosome and the genetic information it contains. In an article published in the journal Genes and Development, scientists from the Laboratory of Biology and Modelling of the Cell (LBMC - CNRS/ENS de Lyon), in collaboration with teams from the USA, have further characterized a mechanism that puts genome stability at risk. These results will enable a better understanding of chromosomal rearrangements revealed by new sequencing techniques in various organisms and in certain pathological situations.

Abstract

Punctuated bursts of structural genomic variations (SVs) have been described in various organisms, but their etiology remains incompletely understood. Homologous recombination (HR) is a template-guided mechanism of repair of DNA double-strand breaks and stalled or collapsed replication forks. We recently identified a DNA break amplification and genome rearrangement pathway originating from the endonucleolytic processing of a multi-invasion (MI) DNA joint molecule formed during HR. Genome-wide approaches confirmed that multi-invasion-induced rearrangement (MIR) frequently leads to several repeat-mediated SVs and aneuploidies. Using molecular and genetic analysis and a novel, highly sensitive proximity ligation-based assay for chromosomal rearrangement quantification, we further delineate two MIR subpathways. MIR1 is a universal pathway occurring in any sequence context, which generates secondary breaks and frequently leads to additional SVs. MIR2 occurs only if recombining donors exhibit substantial homology and results in sequence insertion without additional breaks or SVs. The most detrimental MIR1 pathway occurs late on a subset of persisting DNA joint molecules in a PCNA/Polδ-independent manner, unlike recombinational DNA synthesis. This work provides a refined mechanistic understanding of these HR-based SV formation pathways and shows that complex repeat-mediated SVs can occur without displacement DNA synthesis. Sequence signatures for inferring MIR1 from long-read data are proposed.

Reference 

Delineation of two multi-invasion-induced rearrangement pathways that differently affect genome stability. Diedre Reitz, Yasmina Djeghmoum, Ruth A. Watson, Pallavi Rajput, Juan Lucas Argueso, Wolf-Dietrich Heyer and Aurèle Piazza. Genes and Development, August 4, 2023. 
DOI : 10.1101/gad.350618.123

illustration credits: A. Piazza