Utilizing insights of DNA repair machinery to discover MMEJ deletions and novel mechanisms.

Autor:	Kadam A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Shilo S; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Naor H; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Wainstein A; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Brilon Y; Sequentify Ltd., 10 Moti Kind St., 5th Floor, Rehovot 7638519, Israel., Feldman T; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Minden M; Princess Margaret Cancer Centre, University Health Network (UHN), Department of Medical Oncology & Hematology, Toronto, ON M5G 2C4, Canada., Kaushansky N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Chapal-Ilani N; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel., Shlush L; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.; Molecular Hematology Clinic Maccabi Healthcare Services, Tel Aviv 6812509, Israel.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2024 Nov 28. Date of Electronic Publication: 2024 Nov 28.
DOI:	10.1093/nar/gkae1132
Abstrakt:	We developed Del-read, an algorithm targeting medium-sized deletions (6-100 bp) in short-reads, which are challenging for current variant callers relying on alignment. Our focus was on Micro-Homolog mediated End Joining deletions (MMEJ-dels), prevalent in myeloid malignancies. MMEJ-dels follow a distinct pattern, occurring between two homologies, allowing us to generate a comprehensive list of MMEJ-dels in the exome. Using Del-read, we identified numerous novel germline and somatic MMEJ-dels in BEAT-AML and TCGA-breast datasets. Validation in 672 healthy individuals confirmed their presence. These novel MMEJ-dels were linked to genomic features associated with replication stress, like G-quadruplexes and minisatellite. Additionally, we observed a new category of MMEJ-dels with an imperfect-match at the flanking sequences of the homologies, suggesting a mechanism involving mispairing in homology alignment. We demonstrated robustness of the repair system despite CRISPR/Cas9-induced mismatches in the homologies. Further analysis of the canonical ASXL1 deletion revealed a diverse array of these imperfect-matches. This suggests a potentially more flexible and error-prone MMEJ repair system than previously understood. Our findings highlight Del-read's potential in uncovering previously undetected deletions and deepen our understanding of repair mechanisms. (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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