Delineation of two multi-invasion-induced rearrangement pathways that differently affect genome stability.

bioRxiv

Univ Lyon, ENS, UCBL, CNRS, INSERM, Laboratory of Biology and Modelling of the Cell, UMR5239, U 1210, F-69364, Lyon, France.

Published: March 2023

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 sequencing 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 sub-pathways. 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 break or SV. 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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10055120PMC
http://dx.doi.org/10.1101/2023.03.15.532751DOI Listing

Publication Analysis

Top Keywords

multi-invasion-induced rearrangement
8
dna joint
8
frequently leads
8
repeat-mediated svs
8
dna synthesis
8
dna
6
delineation multi-invasion-induced
4
rearrangement
4
rearrangement pathways
4
pathways differently
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!