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Levels of <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>-mA undergo drastic fluctuation during early embryogenesis, indicative of active regulation. Here we show that the 2-oxoglutarate-dependent oxygenase ALKBH1 functions as a nuclear eraser of <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>-mA in unpairing regions (e.g., SIDD, <jats:underline>S<\/jats:underline>tress-<jats:underline>I<\/jats:underline>nduced <jats:underline>D<\/jats:underline>NA Double Helix <jats:underline>D<\/jats:underline>estabilization regions) of mammalian genomes. Enzymatic profiling studies revealed that ALKBH1 prefers bubbled or bulged DNAs as substrate, instead of single-stranded (ss-) or double-stranded (ds-) DNAs. Structural studies of ALKBH1 revealed an unexpected \u201cstretch-out\u201d conformation of its \u201cFlip1\u201d motif, a conserved element that usually bends over catalytic center to facilitate substrate base flipping in other DNA demethylases. Thus, lack of a bending \u201cFlip1\u201d explains the observed preference of ALKBH1 for unpairing substrates, in which the flipped <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>-mA is primed for catalysis. Co-crystal structural studies of ALKBH1 bound to a 21-mer bulged DNA explained the need of both flanking duplexes and a flipped base for recognition and catalysis. Key elements (e.g., an ALKBH1-specific \u03b11 helix) as well as residues contributing to structural integrity and catalytic activity were validated by structure-based mutagenesis studies. Furthermore, ssDNA-seq and DIP-seq analyses revealed significant co-occurrence of base unpairing regions with <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>-mA in mouse genome. Collectively, our biochemical, structural and genomic studies suggest that ALKBH1 is an important DNA demethylase that regulates genome <jats:italic>N<\/jats:italic><jats:sup>6<\/jats:sup>-mA turnover of unpairing regions associated with dynamic chromosome regulation.<\/jats:p>","DOI":"10.1038\/s41422-019-0237-5","type":"journal-article","created":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T09:02:48Z","timestamp":1581498168000},"page":"197-210","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["Mammalian ALKBH1 serves as an N6-mA demethylase of unpairing DNA"],"prefix":"10.1038","volume":"30","author":[{"given":"Min","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raman","family":"Nelakanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaochao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6741-293X","authenticated-orcid":false,"given":"Haitao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,2,12]]},"reference":[{"key":"237_CR1","doi-asserted-by":"publisher","first-page":"research0007.1","DOI":"10.1186\/gb-2001-2-4-comment1005","volume":"2","author":"LAAEV Koonin","year":"2001","unstructured":"Koonin, L. 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