UNDERSTANDING THE BROAD SUBSTRATE SPECIFICITY OF ALKA AT THE ATOMIC LEVEL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在细胞内，DNA不断受到外源环境毒素和细胞代谢物的攻击，这些物质可以产生各种共价核苷酸修饰。如果不加以纠正，这些损伤可能会导致突变，影响到基因组功能的几乎所有方面，包括转录、DNA复制和重组，以及细胞周期进展和凋亡等非基因组过程。细胞对这类病变管理不善导致的突变是癌症的原因。为了应对DNA损伤构成的威胁，所有细胞都进化了修复机制，负责定位受损的核苷酸并纠正它们。DNA中的大多数单碱基修饰都是由碱基切除修复途径(BER)的酶(糖基酶)纠正的。然而，在碱基切除过程开始之前，修复酶就必须询问数百万个未受损的DNA碱基对，才能定位一个受损的碱基；这是一个典型的大海捞针的问题。这种详尽的全基因组搜索对DNA修复系统来说是一项真正艰巨的任务，它必须进化出能够以非凡的准确性和效率追踪病变的酶。这个子项目利用化学、生物化学和结构生物学的组合来更好地了解BER的酶如何在大量正常DNA中识别DNA损伤，以及酶修复这些损伤的机制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Inside cells, DNA is under constant attack by exogenous environmental toxins and cellular metabolites, insults that can produce various covalent nucleobase modifications. Left uncorrected, these lesions can cause mutations affecting nearly all aspects of genome function, including transcription, DNA replication and recombination, and also non-genomic processes such as cell cycle progression and apoptosis. The mutations that result from cellular mismanagement of such lesions are the cause of cancer. To counter the threat posed by DNA lesions, all cells have evolved repair mechanisms charged with the responsibility for locating damaged nucleotides and correcting them. Most single base modifications in DNA are corrected by enzymes (glycosylases) of the base excision repair pathway (BER). Even before the base excision process can begin, however, the repair enzymes must interrogate millions of base pairs of undamaged DNA in order to locate one damaged nucleobase; a classic needle in the haystack problem. This exhaustive full genome search presents a truly formidable task for the DNA repair system, which must evolve enzymes that can track down lesions with exceptional accuracy and efficiency. This subproject utilizes a combination of chemistry, biochemistry, and structural biology to better understand how the enzymes of the BER identify DNA lesions within the vast excess of normal DNA, as well as the mechanisms of the enzymatic repair of such lesions.