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Characterization of a single nucleotide polymorphism in the microRNA-146a and susceptibility to colorectal cancer

Grant number: 15/19924-3
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2015
Effective date (End): October 31, 2016
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Manoela Marques Ortega
Grantee:Jéssica Silva dos Santos
Home Institution: Universidade São Francisco (USF). Campus Bragança Paulista. Bragança Paulista , SP, Brazil

Abstract

Mutations and single nucleotide polymorphisms (SNPs) in DNA repair genes have been described in colorectal cancer (CRC). One of the mainly DNA repair pathways is homologous recombination (HR). When HR is altered by gene mutation, cells are not able to perform DNA repair, resulting in apoptosis or tumorigenesis. The lysine methylation of histone proteins affects many aspects of the chromosome biology, such as silencing, transcription, recombination and response to DNA damage. DOT1L gene produces a methyltransferase protein responsible for histone H3K79 methylation, which was described to be important for both HR repair and DNA damage prevention by recruiting 53BP1 protein to the DNA Double-strand breaks (DSBs). DOT1L gene mutations resulted in the elongation of telomeres, aneuploidy and defects in cell proliferation. One SNP in DOT1L gene was recently described in a family with hereditary gastric cancer. XRCC3 gene encodes a Rad51 protein family that participates in repair by HR pathway. The SNP g.21071C>T in XRCC3 gene (rs861539) was extensively studied in CRC in different populations with contrasting results regarding risk for the disease. However, there are no studies for any SNPs in XRCC3 gene in the Brazilian population. The mechanism by which DNA repair is mediated by Dot1L and the relation with Xrcc3 is not complete elucidated yet. It has been known that Xrcc3 protein physically interacts with RAD51C and DOT1L-deficient cells resulted in Rad51 deficiency in DSBs. There are no studies correlating DOT1L and XRCC3 SNPs together and increased risk for CRC. SNPs in microRNAs (miRNAs) have been described in gastrointestinal cancer and CRC. The polymorphism located in the mature sequence of miRNA-146a (rs2910164) has been studied in CRC in different populations with and without increased risk for the disease, but not in the Brazilian population. The miR-146a is considerably interesting because it is able to regulate BRCA1 and BRCA2 genes, both involved in DNA repair by HR. Thus, the aim of this study is identify and investigate the role of SNPs in DOT1L and XRCC3 by real time polymerase chain reaction (RT-PCR) and identify and characterize the SNP rs2910164 in miRNA-146a and CRC susceptibility in Brazilian population.