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While BER and active demethylation converge at the generation of AP sites, catalyzed by DNA glycosylases such as thymine DNA glycosylase (TDG), the relative contribution of each pathway to AP site formation and the cellular fate of these lesions remain unresolved. Using APE1-deficient mouse embryonic stem cells (mESCs), with inducible TDG depletion, we reveal that TDG activity accounts for a substantial fraction of AP sites in mESCs, establishing a direct link between active DNA demethylation and APE1-mediated BER. We demonstrate that APE1 is essential for mESC differentiation, underscoring its role in processing AP sites generated during epigenetic reprogramming. Through a genome-wide CRISPR\/Cas9 screen designed to map the broader functional interactome of APE1, we identified unexpected genetic dependencies that extend beyond DNA repair. We also found that DNA double-strand break repair factors act outside their canonical pathways, cooperating with nucleotide excision repair and translesion synthesis to compensate for the loss of APE1. These findings highlight novel compensatory DNA end-processing mechanisms that safeguard genomic integrity in the absence of APE1, revealing a high level of plasticity of DNA repair in mESCs.<\/jats:p>","DOI":"10.1093\/nar\/gkag921","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:43:35Z","timestamp":1789213415000},"source":"Crossref","is-referenced-by-count":0,"title":["Abasic site repair in APE1-deficient mouse embryonic stem cells: a matter for the MRN complex and ATM signaling"],"prefix":"10.1093","volume":"54","author":[{"given":"Alexandra M","family":"Hrovat","sequence":"first","affiliation":[{"name":"Department of Biomedicine, University of Basel , Basel 4058 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1668-7316","authenticated-orcid":false,"given":"Faiza","family":"Noreen","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Basel , Basel 4058 ,","place":["Switzerland"]},{"name":"Swiss Institute of Bioinformatics , Basel 4031 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6630-861X","authenticated-orcid":false,"given":"Simon D","family":"Schwarz","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, University of Basel , Basel 4058 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezgi M","family":"Aksu","sequence":"additional","affiliation":[{"name":"Proteomics and Modomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), and the Central Norway Regional Health Authority , Trondheim 7491 ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3517-3481","authenticated-orcid":false,"given":"Anna","family":"Ku\u015bnierczyk","sequence":"additional","affiliation":[{"name":"Proteomics and Modomics Core Facility (PROMEC), Norwegian University of Science and Technology (NTNU), and the Central Norway Regional Health Authority , Trondheim 7491 ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1837-144X","authenticated-orcid":false,"given":"Navnit K","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, ETH Zurich , Zurich 8092 ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6808-5950","authenticated-orcid":false,"given":"Shana J","family":"Sturla","sequence":"additional","affiliation":[{"name":"Department of Health Sciences and Technology, ETH Zurich , Zurich 8092 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