QuadCleave: Enzymatic cleavage and analysis of DNA G-quadruplexes.

2026 · doi:10.64898/2026.05.15.725486
preprint OA: closed
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This paper describes QuadCleave, an inexpensive two-enzyme method using Mismatch Endonuclease I followed by HaeIII to selectively cleave and thereby confirm formation of DNA G-quadruplexes and determine repeat copy number. The authors report that cleavage patterns allow G4-forming sequences to be distinguished, including cases where a sequence could also form GG/CC base pairs, with concurrent cleavage by both enzymes indicating a G4-forming sequence. A key demonstration involves C9ORF72 oligodeoxynucleotides, the repeat expansion mutation implicated in ALS and frontotemporal dementia. The paper’s limitation is that its validation is focused on experimentally cleaving defined oligodeoxynucleotide sequences rather than directly assessing broader genomic or tissue contexts. The paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.

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Abstract

Prediction of G-quadruplexes (G4), noncanonical DNA secondary structures containing guanine tetrads, can have profound relevance across cancer, neurodegenerative and other genetic diseases, but require experimental validation by instrument intensive methods including CD spectroscopy, fluorescence, NMR, or crystallography. We report a novel, inexpensive, efficient and scalable 2-enzyme system for confirmation of G4 formation and copy number repeat count. First, QuadCleave, in which Mismatch Endonuclease I was used to repeatably, site-specifically and selectively cleave oligodeoxynucleotides containing exclusively G4-forming sequences. Second, HaeIII enzyme identified G4-forming sequences that can also generate GG/CC base pairs, and a sequence’s cleavage by both established it in C9ORF72, the most mutated gene in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These findings establish ubiquitously accessible experimental validation of G4 forming sequences and their copy number repeat assessment, with specificity to C9ORF72 oligodeoxynucleotides whose repeat expansion has critical clinical implications in a subpopulation of ALS and FTD patients.
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Abstract Prediction of G-quadruplexes (G4), noncanonical DNA secondary structures containing guanine tetrads, can have profound relevance across cancer, neurodegenerative and other genetic diseases, but require experimental validation by instrument intensive methods including CD spectroscopy, fluorescence, NMR, or crystallography. We report a novel, inexpensive, efficient and scalable 2-enzyme system for confirmation of G4 formation and copy number repeat count. First, QuadCleave, in which Mismatch Endonuclease I was used to repeatably, site-specifically and selectively cleave oligodeoxynucleotides containing exclusively G4-forming sequences. Second, HaeIII enzyme identified G4-forming sequences that can also generate GG/CC base pairs, and a sequence’s cleavage by both established it in C9ORF72, the most mutated gene in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These findings establish ubiquitously accessible experimental validation of G4 forming sequences and their copy number repeat assessment, with specificity to C9ORF72 oligodeoxynucleotides whose repeat expansion has critical clinical implications in a subpopulation of ALS and FTD patients. Competing Interest Statement The work has been filed for patent with the United States Patent and Trademark Office (USPTO) with US Patent Application No. 63/966,755.

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