On the formation of a new full-length DNA with non-canonical backbone by spermine mediated strand cleavage at abasic (AP) site in duplex DNA
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[EMBARGOED UNTIL 12/01/2025] Abasic (Ap) sites are among the most prevalent DNA lesions, resulting from the loss of a nucleobase. These sites exhibit chemical reactivity and can lead to strand cleavage via ?-elimination, which is catalyzed by various factors, including biological amines. In this study, we investigate the products formed during spermine-mediated strand cleavage at Ap sites. Spermine, a naturally occurring polyamine, facilitates the formation of a reactive ?,?-unsaturated iminium ion intermediate (3'ddR-Sp+) at the strand break. This intermediate reacts with exocyclic amine groups of nucleobases to produce unique low-molecular-weight interstrand crosslinks (LMW ICLs). In this thesis, we report the discovery of a novel "re-ligated" product formed through the 1,4-Michael addition of guanine's exocyclic amine group to the iminium ion intermediate. The ligated product exhibits remarkable stability under physiological conditions and resists cleavage by most human DNA repair enzymes, including APE1 and Fpg, but is effectively processed by bacterial endonuclease IV. Our findings highlight the biochemical consequences of spermine-mediated Ap site cleavage and reveal a previously unrecognized DNA lesion with potential implications for genomic stability and cellular repair mechanisms. These results provide critical insights into the reactivity of Ap sites and their repair pathways, advancing our understanding of DNA damage and its biological consequences.
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M.S.