title: BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III.
abstract: Proteins involved in DNA repair, or its coordination with DNA replication and mitosis through cell cycle checkpoints, are vital in the concerted cellular response to DNA damage that maintains the integrity of the genome. The "BRCT" domain (BRCA1 carboxy terminal) was noted as a putative protein-protein interaction motif in the breast cancer suppressor gene, BRCA1, and subsequently identified in over 50 proteins involved in DNA repair, recombination, or cell cycle control. The heterodimer of the DNA repair proteins, XRCC1 and DNA ligase III, was the first example of a functional interaction via BRCT modules. The only three-dimensional crystal structure of a BRCT domain was solved for this region of XRCC1. Key amino acid residues mediating the interaction with DNA ligase III were identified here by targeted mutagenesis of the XRCC1 BRCT domain. The consequences of these mutations on protein folding were assessed. A structural model of the DNA ligase III BRCT domain was constructed and similarly tested by mutation of corresponding residues required for the interaction with XRCC1. These data identify the XRCC1-DNA ligase III heterodimer interface and provide the first demonstration of the surface contacts coordinating a functional BRCT-BRCT protein interaction.
authors.affiliation: Mutagenesis Laboratory, Imperial Cancer Research Fund, Clare Hall Laboratories, Blanche Lane, South Mimms, Hertfordshire, EN6 3LD, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dulic
authors.forename: P A
authors.initials: PA
authors.lastname: Bates
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: S R
authors.initials: SR
authors.lastname: Martin
authors.forename: P S
authors.initials: PS
authors.lastname: Freemont
authors.forename: T
authors.initials: T
authors.lastname: Lindahl
authors.forename: D E
authors.initials: DE
authors.lastname: Barnes
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002942:Circular Dichroism; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D013816:Thermodynamics; D014364:Tryptophan / Q000235:genetics; D000076105:X-ray Repair Cross Complementing Protein 1; D029867:Xenopus Proteins
chemical_list: D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D010446:Peptide Fragments; D000075223:Poly-ADP-Ribose Binding Proteins; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D029867:Xenopus Proteins; D014364:Tryptophan; D011088:DNA Ligases; D000072481:DNA Ligase ATP; C000618816:DNA ligase III alpha protein, Xenopus; C000618817:LIG3 protein, human