ArticleNucleic acids research2025
TDP1 splice-site mutation causes HAP1 cell hypersensitivity to topoisomerase I inhibition.
Article in Nucleic acids research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- The Influence of TDP1 Inhibitor Usnic Acid Derivative OL9-116 on the Effects of Topotecan in Human Cells.Current issues in molecular biology · 2026Article
- Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay.EMBO molecular medicine · 2026Article
- The evolving landscape of antibody-drug conjugates (ADCs) for treatment of prostate cancer.NPJ precision oncology · 2025Review
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6 authors.
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Abstract
HAP1 is a near-haploid human cell line commonly used for mutagenesis and genome editing studies due to its hemizygous nature. We noticed an unusual hypersensitivity of HAP1 to camptothecin, an antineoplastic drug that stabilizes topoisomerase I cleavage complexes (TOP1ccs). We have attributed this hypersensitivity to a deficiency of TDP1, a key phosphodiesterase involved in resolving abortive TOP1ccs. Through whole-exome sequencing and subsequent restoration of TDP1 protein via CRISPR-Cas9 endogenous genome editing, we demonstrate that TDP1 deficiency and camptothecin hypersensitivity in HAP1 cells are a result of a splice-site mutation (TDP1 c.660-1G > A) that causes exon skipping and TDP1 loss of function. The lack of TDP1 in HAP1 cells should be considered when studying topoisomerase-associated DNA lesions and when generalizing mechanisms of DNA damage repair using HAP1 cells. Finally, we also report the generation of HAP1 STAR clones with restored TDP1 expression and function, which may be useful in further studies to probe cellular phenotypes relating to TOP1cc repair.
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