Genome-wide structural variant landscape following HDR-enhanced CRISPR editing in human hematopoietic stem and progenitor cells
- 1Institut de Recherche en Immunologie et Cancerologie, Universite de Montreal, Canada
Abstract
DNA-PK inhibitors (DNA-PKi) have emerged as potent enhancers of homology-directed repair (HDR) in genome editing, however, recent studies have reported that such inhibitors can induce large-scale structural variations (SVs) raising safety concerns. To investigate factors influencing SV induction in human hematopoietic stem and progenitor cells (HSPCs), we employed a combination of on-target long-read nanopore sequencing and unbiased genome wide detection of SVs using Strand-seq. Our results show that editing alone results in a high frequency of large on-target deletions which were modestly increased by DNA-PK inhibition and could be mitigated using DNA polQ inhibitors. Genome-wide SVs were also induced at low frequencies by editing but were not substantially increased with DNA-PKi. SVs including translocations were, however, increased with multiple simultaneous editing. Our results highlight that edit-induced SVs are not limited to DNA-PKi enhanced protocols, thus careful assessment will be critical to ensure the safety of any edited therapeutic cell product.
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BibTeX
@misc{cloarecung2026genomewide,
title = {{Genome-wide structural variant landscape following HDR-enhanced CRISPR editing in human hematopoietic stem and progenitor cells}},
author = {F.-M. Cloarec-Ung and G. Sauvageau and H. M. Sheppard and P. M. Lansdorp and D. J. Knapp},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.13.732078},
url = {https://www.biorxiv.org/content/10.64898/2026.06.13.732078v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genome-wide structural variant landscape following HDR-enhanced CRISPR editing in human hematopoietic stem and progenitor cells
AU - F.-M. Cloarec-Ung
AU - G. Sauvageau
AU - H. M. Sheppard
AU - P. M. Lansdorp
AU - D. J. Knapp
PY - 2026
DA - 2026/06/13
PB - bioRxiv
DO - 10.64898/2026.06.13.732078
UR - https://www.biorxiv.org/content/10.64898/2026.06.13.732078v2
AB - DNA-PK inhibitors (DNA-PKi) have emerged as potent enhancers of homology-directed repair (HDR) in genome editing, however, recent studies have reported that such inhibitors can induce large-scale structural variations (SVs) raising safety concerns. To investigate factors influencing SV induction in human hematopoietic stem and progenitor cells (HSPCs), we employed a combination of on-target long-read nanopore sequencing and unbiased genome wide detection of SVs using Strand-seq. Our results show that editing alone results in a high frequency of large on-target deletions which were modestly increased by DNA-PK inhibition and could be mitigated using DNA polQ inhibitors. Genome-wide SVs were also induced at low frequencies by editing but were not substantially increased with DNA-PKi. SVs including translocations were, however, increased with multiple simultaneous editing. Our results highlight that edit-induced SVs are not limited to DNA-PKi enhanced protocols, thus careful assessment will be critical to ensure the safety of any edited therapeutic cell product.
ER -