Three prime untranslated regions (3'UTRs) of
messenger RNAs (mRNAs) often contain regulatory sequences that can cause post-transcriptional
RNA silencing. Such 3'-UTRs often contain binding sites for
microRNAs (miRNAs). By binding to specific sites within the 3'-UTR, miRNAs can decrease gene expression of various mRNAs by either inhibiting
translation or directly causing degradation of the transcript.
MicroRNAs (miRNAs) appear to regulate the expression of more than 60% of
protein coding genes of the human genome. One microRNA,
miR-210, represses RAD52. As noted by Devlin et al., miR-210 is up-regulated in most solid tumors and negatively affects the clinical outcome. The 3'-UTR of RAD52 also has a binding site for the microRNA
let-7. Women with a
single-nucleotide polymorphism (SNP) in the binding site for let-7 (rs7963551), that causes reduced binding of let-7, likely have increased expression of RAD52 (as was shown for this SNP in liver). Women with this SNP in the 3'UTR of RAD52 showed a reduced breast cancer risk with an
odds ratio of 0.84, 95% confidence interval of 0.75-0.95. In a Han Chinese population, the same SNP as above in the 3'-UTR of RAD52 binding site for let-7 (rs7963551) reduced the risk of glioma. The risk of glioma associated with the RAD52 rs7963551 genotype had an odds ratio (compared to those without the SNP) of 0.44 for those older than 41 years, and an odds ratio of 0.58 for those 41 years or younger. Li et al. They found two RAD52 microRNA binding sites that were frequently altered and had an effect on colon cancer risk. Individuals with a homozygous or heterozygous SNP in rs1051669 were at increased risk of colon cancer (OR 1.78, 95% CI 1.13–2.80, p = 0.01 for homozygotes and OR 1.72, 95% CI 1.10–2.692, p = 0.02 for heterozygotes). Heterozygous carriers of the other RAD52 SNP (rs11571475) were at decreased risk of colon cancer (OR 0.76, 95% CI 0.58–1.00, p = 0.05). Of 21 genes in the
homologous recombinational repair pathway and 7 genes in the
non-homologous end joining pathway examined, the only SNPs found in microRNA binding regions which were both at high enough frequency to evaluate and which affected risks of colon cancer, were the two in RAD52 and one in
MRE11A. DNA damage appears to be the primary underlying cause of cancer, and deficiencies in DNA repair appear to underlie many forms of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase
mutational errors during
DNA replication due to error-prone
translesion synthesis. Excess DNA damage may also increase
epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations may give rise to
cancer. The frequent microRNA-induced increase or deficiency of
RAD52-mediated DNA repair due to microRNA binding alterations likely contributes to either the prevention or progression of breast, brain, liver or colon cancers. == Interactions ==