DNA-repair protein Xrcc1 functions in the repair of single-strand DNA breaks in mammalian cells and forms a repair complex with beta-Pol, ligase III and PARP []. The NMR solution structure of the Xrcc1 N-terminal domain (Xrcc1 NTD) shows that the structural core is a β-sandwich with β-strands connected by loops, three helices and two short two-stranded β-sheets at each connection side. The Xrcc1 NTD specifically binds single-strand break DNA (gapped and nicked) and a gapped DNA-beta-Pol complex [].
XRCC1 plays a key role in multiple DNA repair pathways by acting as a scaffold that binds to both DNA single strand breaks and gaps, poly (ADP-ribose) and to numerous DNA repair enzymes. It forms homodimers and interacts with polynucleotide kinase (PNK), DNA polymerase-beta (POLB), DNA ligase III (LIG3), APTX, APLF, and APEX1 [, ]. XRCC1 contains an N-terminal XRCC1-specific domain and two BRCT domains. This entry corresponds to the first (central) BRCT domain []. This domain has been shown to interact with poly(ADP-ribosyl)ated (PARylated) PARP1. Inactivation of the central X1BR1 domain results in DNA damage hypersensitivity due to a defect in S phase-dependent DNA repair [].
The protein APLF (aprataxin and PNK-like factor or Xip1; ) is a nuclease involved in single-strand and double-strand DNA break repair []. It has endo- and exonuclease activities and contains a FHA (forkhead-associated) domain and zinc-finger-like CYR motifs []. APLF interacts with XRCC1 and XRCC4 via its FHA domain [, ].
This entry includes bifunctional polynucleotide phosphatase/kinase PNKP from animals. PNKP plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining (NHEJ) and base excision repair (BER) pathways. It has been shown that the DNA 3'-phosphatase activity of PNKP takes precedence over its DNA 5'-kinase activity in vitro []. It contains a forkhead-associated domain, which is a protein-protein interaction domain required for the association of PNKP with CK2-phosphorylated XRCC1 and XRCC4, and independent DNA 3'-phosphatase and 5'-kinase domains [].
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography, it comprises a four-stranded parallel β-sheet surrounded by three α-helices, which form an autonomously folded domain [].
Proteins containing a galactose-binding domain-like fold can be found in several different protein families, in both eukaryotes and prokaryotes. The common function of these domains is to bind to specific ligands, such as cell-surface-attached carbohydrate substrates for galactose oxidase and sialidase [], phospholipids on the outer side of the mammalian cell membrane for coagulation factor Va [], membrane-anchored ephrin for the Eph family of receptor tyrosine kinases [], and a complex of broken single-stranded DNA and DNA polymerase beta for XRCC1 []. The structure of the galactose-binding domain-like members consists of a β-sandwich, in which the strands making up the sheets exhibit a jellyroll fold [].This entry represents a galactose-binding domain-like fold domain found in endo-alpha-N-acetylgalactosaminidases from bacteria.
Proteins containing a galactose-binding-like domain fold can be found in several different protein families, in both eukaryotes and prokaryotes. The common function of these domains is to bind to specific ligands, such as cell-surface-attached carbohydrate substrates for galactose oxidase and sialidase [], phospholipids on the outer side of the mammalian cell membrane for coagulation factor Va [], membrane-anchored ephrin for the Eph family of receptor tyrosine kinases [], and a complex of broken single-stranded DNA and DNA polymerase beta for XRCC1 [].The structure of the galactose-binding-like domain members consists of a β-sandwich, in which the strands making up the sheets exhibit a jelly roll fold. There is a high degree of similarity in the β-sandwich and in the loops between different family members, despite an often low level of sequence similarity.
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. BRCT domains are often found as tandem-repeat pairs []. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography [].Structures of the BRCA1 BRCT domains revealed a basis for a widely utilised head-to-tail BRCT-BRCT oligomerization mode []. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants [].
Aprataxin is a DNA-binding protein involved in single-strand and double-strand DNA break repair, and base excision repair [, , ]. In yeast the aprataxin orthologue is known as Hnt3 (Hit family protein 3) []. Aprataxin is a member of the histidine triad (HIT) superfamily of nucleotide hydrolases and transferases, named for their characteristic HxHxHxx catalytic motif, where x is a hydrophobic amino acid []. It also contains an N-terminal forkhead associated (FHA) domain, which is thought to mediate interactions with the ligase cofactors XRCC1 and XRCC4, and a C-terminal zinc finger domain implicated in DNA binding [, ].Aprataxin repairs adenylated RNA-DNA junctions []. It resolves abortive DNA ligation intermediates formed either at base excision sites, or when DNA ligases attempt to repair non-ligatable breaks induced by reactive oxygen species. It catalyses the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined []. Mutations in the aprataxin gene cause the neurological disorder ataxia oculomotor apraxia-1 (AOA1).This entry also includes the Aprataxin-like protein BHLH140.
