Abstract
Partner and Localizer of BRCA2 or PALB2 is a typical tumor suppressor protein, that responds to DNA double stranded breaks through homologous recombination repair. Heterozygous mutations in PALB2 are known to contribute to the susceptibility of breast and ovarian cancer. However, there is no comprehensive study characterizing the structural and functional impacts of SNPs located in the PALB2 gene.Therefore, it is of interest to document a comprehensive analysis of coding and non-coding SNPs located at the PALB2 loci using in silico tools. The data for 1455 non-synonymous SNPs (nsSNPs) located in the PALB2 loci were retrieved from the dbSNP database. Comprehensive characterization of the SNPs using a combination of in silico tools such as SIFT, PROVEAN, PolyPhen, PANTHER, PhDSNP, Pmut, MutPred 2.0 and SNAP-2, identified 28 functionally important SNPs. Among these, 16 nsSNPs were further selected for structural analysis using conservation profile and protein stability. The most deleterious nsSNPs were documented within the WD40 domain of PALB2. A general outline of the structural consequences of each variant was developed using the HOPE project data. These 16 mutant structures were further modelled using SWISS Model and three most damaging mutant models (rs78179744, rs180177123 and rs45525135) were identified. The non-coding SNPs in the 3’ UTR region of the PALB2 gene were analyzed for altered miRNA target sites. The comprehensive characterization of the coding and non-coding SNPs in the PALB2 locus has provided a list of damaging SNPs with potential disease association. Further validation through genetic association study will reveal their clinical significance.
Highlights
PALB2, a 1186 amino acid residue protein, is mainly responsible for the coadjuvancy of BRCA1 and BRCA2 in the DNA damage response pathway [1]
PALB2 consists of several protein domains including N-terminal coiledcoil domain-that interacts with BRCA1, C terminal WD40 domainthat interacts with BRCA2 and Chromatin Association Motif (ChAM)-that promotes chromatin association [3]
Further analysis was carried out using the PhDSNP (Predictor of human Deleterious Single Nucleotide Polymorphisms), a multiple sequence based alignment tool to predict whether a new phenotype derived from a non-synonymous Single nucleotide polymorphisms (SNPs) (nsSNPs) can be related to genetic disease in humans [25]
Summary
PALB2, a 1186 amino acid residue protein, (the gene for PALB2 is located on chromosome 16p 12.2) is mainly responsible for the coadjuvancy of BRCA1 and BRCA2 in the DNA damage response pathway [1]. PALB2 was first identified as a BRCA2 interacting protein for recruiting BRCA2 to DNA damage repair sites. Later its contribution to tumor suppression was recognized [2]. PALB2 consists of several protein domains including N-terminal coiledcoil domain-that interacts with BRCA1, C terminal WD40 domainthat interacts with BRCA2 and Chromatin Association Motif (ChAM)-that promotes chromatin association [3]. Impairment of Nterminal coiled-coil domain-BRCA1interaction is associated with breast cancer risk [4]. A single nucleotide change in PALB2 C-terminal domain can disrupt its interaction with BRCA2
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