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DNA ligase IV binds to XRCC4 via a motif located between rather than within its BRCT domains

1998; Elsevier BV; Volume: 8; Issue: 15 Linguagem: Inglês

10.1016/s0960-9822(07)00349-1

1879-0445

Ulf Grawunder, David Zimmer, Michael R. Lieber,

PARP inhibition in cancer therapy

The covalent rejoining of DNA ends at single-stranded or double-stranded DNA breaks is catalyzed by DNA ligases. Four DNA ligase activities (I–IV) have been identified in mammalian cells [[1]Tomkinson AE Levin DS Mammalian DNA ligases.Bioessays. 1997; 19 (98030179): 893-901Crossref PubMed Scopus (97) Google Scholar]. It has recently been demonstrated that DNA ligase IV interacts with and is catalytically stimulated by the XRCC4 protein [2Grawunder U Wilm M Wu X Kulesza P Wilson TE Mann M Lieber MR Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells.Nature. 1997; 388 (97384899): 492-495Crossref PubMed Scopus (509) Google Scholar, 3Critchlow SE Bowater RP Jackson SP Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV.Curr Biol. 1997; 7 (97411152): 588-598Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar], which is essential for DNA double-strand break repair and the genomic rearrangement process of V(D)J recombination [[4]Li Z Otevrel T Gao Y Cheng HL Seed B Stamato TD et al.The XRCC4 gene encodes a novel protein involved in DNA double-strand break repair and V(D)J recombination.Cell. 1995; 83 (96128113): 1079-1089Abstract Full Text PDF PubMed Scopus (385) Google Scholar]. Together, with the finding that the yeast DNA ligase IV homologue is essential for non-homologous DNA end joining [5Wilson TE Grawunder U Lieber MR Yeast DNA ligase IV mediates non-homologous DNA end joining.Nature. 1997; 388 (97384900): 495-498Crossref PubMed Scopus (332) Google Scholar, 6Schär P Hermann G Daly G Lindahl T A newly identified DNA ligase of Saccharomyces cerevisiae involved in RAD52-independent repair of DNA double-strand breaks.Genes Dev. 1997; 11: 1912-1924Crossref PubMed Scopus (171) Google Scholar, 7Teo SH Jackson SP Identification of Saccharomyces cerevisiae DNA ligase IV: involvement in DNA double-strand break repair.EMBO J. 1997; 16 (97447583): 4788-4795Crossref PubMed Scopus (225) Google Scholar], this has led to the hypothesis that mammalian DNA ligase IV catalyzes ligation steps in both of these processes [[8]Grawunder U West RB Lieber MR Antigen receptor gene rearrangement.Curr Opin Immunol. 1998; 10 (98265016): 172-180Crossref PubMed Scopus (87) Google Scholar]. DNA ligase IV is characterized by a unique carboxy-terminal tail comprising two BRCT (BRCA1 carboxyl terminus) domains. BRCT domains were initially identified in the breast cancer susceptibility protein BRCA1 [[9]Koonin EV Altschul SF Bork P Functional motifs.Nat Genet. 1996; 13 (96259550): 266-267Crossref PubMed Scopus (346) Google Scholar], but are also found in other DNA repair proteins [[10]Callebaut I Mornon JP From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair.FEBS Lett. 1997; 400 (97153217): 25-30Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar]. It has been suggested that DNA ligase IV associates with XRCC4 via its tandem BRCT domains and that this may be a general model for protein–protein interactions between DNA repair proteins [[3]Critchlow SE Bowater RP Jackson SP Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA ligase IV.Curr Biol. 1997; 7 (97411152): 588-598Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar]. We have performed a detailed deletional analysis of DNA ligase IV to define its XRCC4-binding domain and to characterize regions essential for its catalytic activity. We find that a region in the carboxy-terminal tail of DNA ligase IV located between rather than within BRCT domains is necessary and sufficient to confer binding to XRCC4. The catalytic activity of DNA ligase IV is affected by mutations within the first two-thirds of the protein including a 67 amino-acid amino-terminal region that was previously thought not to be present in human DNA ligase IV [[11]Wei YF Robins P Carter K Caldecott K Pappin DJC Yu GL et al.Molecular cloning and expression of human cDNAs encoding a novel DNA ligase IV and DNA ligase III, an enzyme active in DNA repair and recombination.Mol Cell Biol. 1995; 15 (95280920): 3206-3216Crossref PubMed Scopus (223) Google Scholar].