Non-homologous end joining shapes the genomic rearrangement landscape of chromothripsis from mitotic errors

Qing Hu, Jose Espejo Valle-Inclán, Rashmi Dahiya, Alison Guyer, Alice Mazzagatti, Elizabeth G. Maurais, Justin L. Engel, Huiming Lu, Anthony J. Davis, Isidro Cortés-Ciriano and Peter Ly ()
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Qing Hu: University of Texas Southwestern Medical Center
Jose Espejo Valle-Inclán: European Bioinformatics Institute, Wellcome Genome Campus
Rashmi Dahiya: University of Texas Southwestern Medical Center
Alison Guyer: University of Texas Southwestern Medical Center
Alice Mazzagatti: University of Texas Southwestern Medical Center
Elizabeth G. Maurais: University of Texas Southwestern Medical Center
Justin L. Engel: University of Texas Southwestern Medical Center
Huiming Lu: University of Texas Southwestern Medical Center
Anthony J. Davis: University of Texas Southwestern Medical Center
Isidro Cortés-Ciriano: European Bioinformatics Institute, Wellcome Genome Campus
Peter Ly: University of Texas Southwestern Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract Mitotic errors generate micronuclei entrapping mis-segregated chromosomes, which are susceptible to catastrophic fragmentation through chromothripsis. The reassembly of fragmented chromosomes by error-prone DNA double-strand break (DSB) repair generates diverse genomic rearrangements associated with human diseases. How specific repair pathways recognize and process these lesions remains poorly understood. Here we use CRISPR/Cas9 to systematically inactivate distinct DSB repair pathways and interrogate the rearrangement landscape of fragmented chromosomes. Deletion of canonical non-homologous end joining (NHEJ) components substantially reduces complex rearrangements and shifts the rearrangement landscape toward simple alterations without the characteristic patterns of chromothripsis. Following reincorporation into the nucleus, fragmented chromosomes localize within sub-nuclear micronuclei bodies (MN bodies) and undergo ligation by NHEJ within a single cell cycle. In the absence of NHEJ, chromosome fragments are rarely engaged by alternative end-joining or recombination-based mechanisms, resulting in delayed repair kinetics, persistent 53BP1-labeled MN bodies, and cell cycle arrest. Thus, we provide evidence supporting NHEJ as the exclusive DSB repair pathway generating complex rearrangements from mitotic errors.

Date: 2024
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DOI: 10.1038/s41467-024-49985-5

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