ABSTRACT
Non-homologous end joining (NHEJ) pathway has pivotal role in repair of double-strand DNA breaks that may lead to carcinogenesis. XRCC4 is one of the essential proteins of this pathway and single-nucleotide polymorphisms (SNPs) of this gene are reported to be associated with cancer risks. In our study, we first used computational approaches to predict the damaging variants of XRCC4 gene. Tools predicted rs79561451 (S110P) nsSNP as the most deleterious SNP. Along with this SNP, we analysed other two SNPs (rs3734091 and rs6869366) to study their association with breast cancer in population of West India. Variant rs3734091 was found to be significantly associated with breast cancer while rs6869366 variant did not show any association. These SNPs may influence the susceptibility of individuals to breast cancer in this population.
Subject(s)
Breast Neoplasms/genetics , DNA-Binding Proteins/genetics , Genetic Association Studies/methods , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Case-Control Studies , Computational Biology/methods , DNA Mutational Analysis/methods , Female , Genetic Predisposition to Disease , Genotype , Humans , India , Middle AgedABSTRACT
Several reports suggest that non-synonymous single nucleotide polymorphisms affect the function of XRCC1 which impairs DNA repair capacity and thus increases risk to diseases like cancer. In our study, we predicted the most damaging nsSNPs using a computational approach and analysed its functional impact on the XRCC1 and LIG3 interaction. SNP rs2307166 was predicted to be deleterious using eight software programs: SIFT, PolyPhen, PANTHER, PhD-SNP, nsSNPAnalyzer, SNPS&GO, SNAP and I-Mutant. Protein structural analysis was performed using Swiss PDB viewer, and PyMOL. Xenoview was used for molecular dynamic simulation and energy minimisation. Finally, PatchDock and FireDock were used to analyse the interactions of XRCC1 and LIG3. By comparing the results we found that the mutant protein has less binding energy and the interacting amino acids than native protein. In silico analysis predicted rs2307166 to be more damaging than three other extensively studied SNPs. Identification of this SNP will help in determining the susceptibility of the individual to cancer, their prognosis and further treatment.
Subject(s)
DNA Ligases , DNA-Binding Proteins , Genetic Predisposition to Disease , Neoplasm Proteins , Neoplasms , Polymorphism, Single Nucleotide , Software , DNA Ligase ATP , DNA Ligases/genetics , DNA Ligases/metabolism , DNA Mutational Analysis/methods , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Databases, Protein , Humans , Mutation , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Poly-ADP-Ribose Binding Proteins , Protein Binding , Sequence Analysis, Protein/methods , X-ray Repair Cross Complementing Protein 1 , Xenopus ProteinsABSTRACT
BACKGROUND: Francisella novicida is a rare cause of human illness despite its close genetic relationship to Francisella tularensis, the agent of tularemia. During April-July 2011, 3 inmates at a Louisiana correctional facility developed F. novicida bacteremia; 1 inmate died acutely. METHODS: We interviewed surviving inmates; reviewed laboratory, medical, and housing records; and conducted an environmental investigation. Clinical and environmental samples were tested by culture, real-time polymerase chain reaction (PCR), and multigene sequencing. Isolates were typed by pulsed-field gel electrophoresis (PFGE). RESULTS: Clinical isolates were identified as F. novicida based on sequence analyses of the 16S ribosomal RNA, pgm, and pdpD genes. PmeI PFGE patterns for the clinical isolates were indistinguishable. Source patients were aged 40-56 years, male, and African American, and all were immunocompromised. Two patients presented with signs of bacterial peritonitis; the third had pyomyositis of the thigh. The 3 inmates had no contact with one another; their only shared exposures were consumption of municipal water and of ice that was mass-produced at the prison in an unenclosed building. Swabs from one set of ice machines and associated ice scoops yielded evidence of F. novicida by PCR and sequencing. All other environmental specimens tested negative. CONCLUSIONS: To our knowledge, this is the first reported common-source outbreak of F. novicida infections in humans. Epidemiological and laboratory evidence implicate contaminated ice as the likely vehicle of transmission; liver disease may be a predisposing factor. Clinicians, laboratorians, and public health officials should be aware of the potential for misidentification of F. novicida as F. tularensis.
