Schellenberg Matthew J, Tumbale Percy P, Williams R Scott
Genome Integrity and Structural Biology Laboratory, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC, 27709, USA.
Prog Biophys Mol Biol. 2015 Mar;117(2-3):157-165. doi: 10.1016/j.pbiomolbio.2015.01.007. Epub 2015 Jan 29.
Eukaryotic DNA ligases seal DNA breaks in the final step of DNA replication and repair transactions via a three-step reaction mechanism that can abort if DNA ligases encounter modified DNA termini, such as the products and repair intermediates of DNA oxidation, alkylation, or the aberrant incorporation of ribonucleotides into genomic DNA. Such abortive DNA ligation reactions act as molecular checkpoint for DNA damage and create 5'-adenylated nucleic acid termini in the context of DNA and RNA-DNA substrates in DNA single strand break repair (SSBR) and ribonucleotide excision repair (RER). Aprataxin (APTX), a protein altered in the heritable neurological disorder Ataxia with Oculomotor Apraxia 1 (AOA1), acts as a DNA ligase "proofreader" to directly reverse AMP-modified nucleic acid termini in DNA- and RNA-DNA damage responses. Herein, we survey APTX function and the emerging cell biological, structural and biochemical data that has established a molecular foundation for understanding the APTX mediated deadenylation reaction, and is providing insights into the molecular bases of APTX deficiency in AOA1.
真核生物DNA连接酶在DNA复制和修复过程的最后一步通过三步反应机制封闭DNA断裂处。如果DNA连接酶遇到修饰的DNA末端，例如DNA氧化、烷基化产物或核糖核苷酸异常掺入基因组DNA产生的修复中间体，该反应机制可能会终止。这种失败的DNA连接反应充当DNA损伤的分子检查点，并在DNA单链断裂修复（SSBR）和核糖核苷酸切除修复（RER）的DNA和RNA-DNA底物中产生5'-腺苷酸化核酸末端。脱嘌呤嘧啶核酸内切酶（APTX）是一种在遗传性神经疾病伴动眼失用性共济失调1型（AOA1）中发生改变的蛋白质，它作为DNA连接酶的“校对器”，在DNA和RNA-DNA损伤反应中直接逆转AMP修饰的核酸末端。在此，我们综述了APTX的功能以及新出现的细胞生物学、结构和生化数据，这些数据为理解APTX介导的去腺苷酸化反应奠定了分子基础，并为深入了解AOA1中APTX缺陷的分子基础提供了线索。
