dna ligase structure mechanism and function pdf

Dna ligase structure mechanism and function pdf

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DNA Ligases: Structure, Function and Mechanism

Introduction

DNA ligases as therapeutic targets

DNA Ligases: Structure, Function and Mechanism

DOI : ATP-dependent ligases have been found in bacteriophages, viruses, archaea, eukaryotes and bacteria. NAD-dependent ligases exist in eubacteria and entomopoxviruses. Both types of ligases share a catalytic core which consists of conserved motifs found in nucleotidyl transferase superfamily. These motifs are essential for adenylation cofactor binding, metal ion coordination, and ligation chemistry, as validated by X-ray crystal structure determination and mutational analyses.

The identification of DNA repair defects in inherited human diseases that are characterized by predisposition to cancer, including inherited forms of colon and breast cancer, provides compelling evidence that the cellular mechanisms that maintain genome stability play a critical role in suppressing cancer formation 1. Since genomic instability is a hallmark feature of sporadic as well as hereditary cancers, it is likely that alterations in one or more of the mechanisms that maintain genome stability occur at some stage during the development of most cancers. Although it has been assumed that these alterations in the DNA damage response contribute, at least in part, to the therapeutic activity of cytotoxic DNA damaging agents such as cis-platinum and doxorubicin, they remain poorly characterized, particularly in sporadic cancers. The recent development of poly ADP-ribose polymerase inhibitors as therapeutics that selectively target the DNA repair defect in hereditary breast cancers has stimulated interest in defining abnormalities in the DNA damage response in sporadic cancers 2 and the development of inhibitors of other DNA repair proteins that may have utility as anti-cancer agents 2. In this review, we summarize our current understanding of the cellular functions of human DNA ligases Table 1 and recent studies that identify DNA ligases as potential biomarkers for abnormal DNA repair and demonstrate the potential clinical utility of DNA ligase inhibitors in cancer treatment. DNA ligases maintain the integrity of the phosphodiester backbone of duplex DNA by catalyzing phosphodiester bond formation 3. All DNA ligases utilize the same three-step reaction mechanism Figure 1.

Bowater; Biochemical and structural characterization of DNA ligases from bacteria and archaea. Biosci Rep 1 October ; 36 5 : e DNA ligases are enzymes that seal breaks in the backbones of DNA, leading to them being essential for the survival of all organisms. DNA ligases have been studied from many different types of cells and organisms and shown to have diverse sizes and sequences, with well conserved specific sequences that are required for enzymatic activity. A significant number of DNA ligases have been isolated or prepared in recombinant forms and, here, we review their biochemical and structural characterization. Here, we review the recent advances that herald new opportunities to alter the biochemical activities of these important enzymes. The recent development of modified derivatives of nucleotides highlights that the continued combination of structural, biochemical and biophysical techniques will be useful in targeting these essential cellular enzymes.

Introduction

Bacteriophage T4 DNA ligase is the first ATP-dependent ligase enzyme to be discovered and is widely used in molecular biology, but its structure remained unknown. Thus, T4 DNA ligase represents a prototype of the larger eukaryotic and archaeal DNA ligases, with a uniquely evolved mode of protein interaction that may be important for efficient DNA replication. They are essential enzymes for life and are found in all kingdoms of life as well as in many viruses 4—6. DNA ligases from eukaryotes, archaea, and some bacteria that play an essential role in replication physically associate with the DNA polymerase processivity factor known as the sliding clamp PCNA and its homologs 7— The ligase-sliding clamp interaction helps recruit DNA ligase to nicks between newly synthesized Okazaki fragments or the sites of DNA lesions, and thereby facilitates completion of DNA replication and repair 11— However, an interaction between virally encoded ligase and a sliding clamp has not been reported.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Hypomorphic LigIV mutations cause extreme radiation sensitivity and immunodeficiency in humans. To better understand the unique features of LigIV function, here we report the crystal structure of the catalytic core of human LigIV in complex with a nicked nucleic acid substrate in two distinct states—an open lysyl-AMP intermediate, and a closed DNA—adenylate form. Results from structural and mutagenesis experiments unveil a dynamic LigIV DNA encirclement mechanism characterized by extensive interdomain interactions and active site phosphoanhydride coordination, all of which are required for efficient DNA nick sealing.

DNA ligase is a specific type of enzyme, a ligase , EC 6. It plays a role in repairing single-strand breaks in duplex DNA in living organisms, but some forms such as DNA ligase IV may specifically repair double-strand breaks i. Single-strand breaks are repaired by DNA ligase using the complementary strand of the double helix as a template, [1] with DNA ligase creating the final phosphodiester bond to fully repair the DNA. The mechanism of DNA ligase is to form two covalent phosphodiester bonds between 3' hydroxyl ends of one nucleotide "acceptor" , with the 5' phosphate end of another "donor". Two ATP molecules are consumed for each phosphodiester bond formed. AMP is required for the ligase reaction, which proceeds in four steps:. Ligase will also work with blunt ends , although higher enzyme concentrations and different reaction conditions are required.


Request PDF | DNA Ligases: Structure, Reaction Mechanism, and Function | With the participation of DNA ligases in multiple different DNA.


DNA ligases as therapeutic targets

Metrics details. By catalyzing the joining of breaks in the phosphodiester backbone of duplex DNA, DNA ligases play a vital role in the diverse processes of DNA replication, recombination and repair. Enzymes of each class comprise catalytic and non-catalytic domains together with additional domains of varying function. DNA ligases are a large family of evolutionarily related proteins that play important roles in a wide range of DNA transactions, including chromosomal DNA replication, DNA repair and recombination, in all three kingdoms of life [ 1 ].

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ATP-dependent DNA ligases

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STRUCTURE AND FUNCTIONS OF ATP-DEPENDENT DNA LIGASES

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DNA ligase

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