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Understanding APE1 cellular functions by the structural preference of exonuclease activities.

ABSTRACT: Mammalian apurinic/apyrimidinic (AP) endonuclease 1 (APE1) has versatile enzymatic functions, including redox, endonuclease, and exonuclease activities. APE1 is thus broadly associated with pathways in DNA repair, cancer cell growth, and drug resistance. Unlike its AP site-specific endonuclease activity in Base excision repair (BER), the 3'-5' exonucleolytic cleavage of APE1 using the same active site exhibits complex substrate selection patterns, which are key to the biological functions. This work aims to integrate molecular structural information and biocatalytic properties to deduce the substrate recognition mechanism of APE1 as an exonuclease and make connection to its diverse functionalities in the cell. In particular, an induced space-filling model emerges in which a bridge-like structure is formed by Arg177 and Met270 (RM bridge) upon substrate binding, causing the active site to adopt a long and narrow product pocket for hosting the leaving group of an AP site or the 3'-end nucleotide. Rather than distinguishing bases as other exonucleases, the hydrophobicity and steric hindrance due to the APE1 product pocket provides selectivity for substrate structures, such as matched or mismatched blunt-ended dsDNA, recessed dsDNA, gapped dsDNA, and nicked dsDNA with 3'-end overhang shorter than 2 nucleotides. These dsDNAs are similar to the native substrates in BER proofreading, BER for trinucleotide repeats (TNR), Nucleotide incision repair (NIR), DNA single-strand breaks (SSB), SSB with damaged bases, and apoptosis. Integration of in vivo studies, in vitro biochemical assays, and structural analysis is thus essential for linking the APE1 exonuclease activity to the specific roles in cellular functions.

SUBMITTER: Liu TC

PROVIDER: S-EPMC8258793 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Understanding APE1 cellular functions by the structural preference of exonuclease activities.

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