A Recql5 mutant facilitates complex CRISPR/Cas9-mediated chromosomal engineering in mouse zygotes

Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5, a crucial member of the DNA hel...

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Bibliographic Details
Published in:Genetics (Austin) 2024-06, Vol.227 (2)
Main Authors: Iwata, Satoru, Nagahara, Miki, Ido, Risako, Iwamoto, Takashi
Format: Article
Language:English
Subjects:
Animals
Brief Investigations
CRISPR-Cas Systems
Mice
Mutation
RecQ Helicases - genetics
RecQ Helicases - metabolism
Zygote - metabolism
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Summary:Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5, a crucial member of the DNA helicase RecQ family involved in DNA replication, transcription, and repair, enabled CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon "chromoanasynthesis." These data show that Recql5 mutant mice could be a powerful tool to analyze the pathogenesis of CCRs (particularly chromoanasynthesis) whose underlying mechanisms are poorly understood. The Recql5 mutants generated in this study are to be deposited at key animal research facilities, thereby making them accessible for future research on CCRs.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1093/genetics/iyae054