H, C, and N backbone resonance assignments of the human DNA ligase 3 DNA-binding domain (residues 257-477).

Printer-friendly versionPrinter-friendly versionPDF versionPDF version
TitleH, C, and N backbone resonance assignments of the human DNA ligase 3 DNA-binding domain (residues 257-477).
Publication TypeJournal Article
Year of Publication2019
AuthorsRoth, BM, Varney, KM, Yang, H, Weber, DJ, Tomkinson, AE
JournalBiomol NMR Assign
Volume13
Issue2
Pagination305-308
Date Published2019 10
ISSN1874-270X
KeywordsDNA, DNA Ligase ATP, Humans, Nuclear Magnetic Resonance, Biomolecular, Poly-ADP-Ribose Binding Proteins, Protein Domains
Abstract

In mammalian cells, the process of DNA ligation is necessary during DNA replication to create an intact "lagging" strand from a series of smaller Okazaki fragments and to repair DNA strand breaks that arise either due to the direct action of a DNA damaging agent or as a consequence of DNA damage excision during DNA repair. In humans, there are three genes that encode for members of the DNA ligase family (LIG1, LIG3 and LIG4) (Ellenberger and Tomkinson in Ann Rev Biochem 77:313-338. 2008). Although these genes code for polypeptides with overlapping functions in the nucleus, the only mitochondrial DNA ligase (DNA ligase IIIα), which is essential for mitochondrial genome maintenance, is encoded by the LIG3 gene (Lakshmipathy and Campbell in Mol Cell Biol 19:3869-3876, 1999; Zong et al. in Mol Cell 61:667-676, 2016) Because mitochondria play a central and multifunctional role in malignant tumor progression, there is emerging interest in targeting key mitochondrial proteins. Notably, there is evidence in pre-clinical models that inhibitors of DNA ligase IIIα, which is frequently up-regulated in cancer, preferentially target cancer cells via their effect on mitochondria (Zong et al. 2016). Since NMR spectroscopy provides unique capabilities for identifying small molecules that bind specifically to DNA ligase IIIα versus the other DNA ligases), the backbone H, C, and N NMR resonance assignments were completed for a 222 amino acid DNA-binding domain of human DNA ligase III. These NMR assignments represent a vital first step towards developing DNA ligase III-selective inhibitors.

DOI10.1007/s12104-019-09896-9
Alternate JournalBiomol NMR Assign
PubMed ID31093909
PubMed Central IDPMC6715534
Grant ListS10 RR023447 / RR / NCRR NIH HHS / United States
P30 CA118100 / CA / NCI NIH HHS / United States
S10 RR029601 / RR / NCRR NIH HHS / United States
P30 CA134274 / CA / NCI NIH HHS / United States
R01 ES012512 / ES / NIEHS NIH HHS / United States
P01 CA092584 / CA / NCI NIH HHS / United States