The Novel Pathogenic Mutation c.849dupT in BRCA2 Contributes to the Nonsense-Mediated mRNA Decay of BRCA2 in Familial Breast Cancer / 한국유방암학회지

In this study, we used next-generation sequencing methods to screen 300 individuals for BRCA1 and BRCA2. A novel mutation (c.849dupT) in BRCA2 was identified in a female patient and her unaffected brothers. This mutation leads to the truncation of BRCA2 functional domains. Moreover, BRCA2 mRNA expression levels in mutation carriers are significantly reduced compared to noncarriers. Immunofluorescence and western blot assays showed that this mutation resulted in reduced BRCA2 protein expression. Thus, we identified a novel mutation that damaged the function and expression of BRCA2 in a family with breast cancer history. The pedigree analysis suggested that this mutation is strongly associated with familial breast cancer. Genetic counsellors suggest that mutation carriers in this family undergo routine screening for breast cancer, as well as other malignancies, such as prostate and ovarian cancer. The effects of this BRCA2 mutation on drug resistance should be taken into consideration during treatment.

mRNA quality control pathways in Saccharomyces cerevisiae.

Efficient production of translation-competent mRNAs involves processing and modification events both in the nucleus and cytoplasm which require a number of complex machineries at both co-transcriptional and posttranscriptional levels. Mutations in the genomic sequence sometimes result in the formation of mutant nonfunctional defective messages. In addition, the enormous amounts of complexities involved in the biogenesis of mRNPs in the nucleus very often leads to the formation of aberrant and faulty messages along with their functional counterpart. Subsequent translation of these mutant and defective populations of messenger RNAs could possibly result in the unfaithful transmission of genetic information and thus is considered a threat to the survival of the cell. To prevent this possibility, mRNA quality control systems have evolved both in the nucleus and cytoplasm in eukaryotes to scrutinize various stages of mRNP biogenesis and translation. In this review, we will focus on the physiological role of some of these mRNA quality control systems in the simplest model eukaryote Saccharomyces cerevisiae.

CUG-BP and 3'UTR sequences influence PARN-mediated deadenylation in mammalian cell extracts

Several mRNAs have been shown to exhibit distinct patterns of poly(A) shortening prior to their decay in vivo. In this study, we show that individual transcripts also demonstrate distinct patterns of deadenylation in in vitro systems derived from HeLa and Jurkat T cell cytoplasmic extracts. The major patterns observed were slow/synchronous and fast/asynchronous poly(A) tail shortening. For all RNA substrates tested, PARN was shown to be the enzyme responsible for the deadenylation patterns that were observed. Sequences in the 3' untranslated regions influenced the deadenylation pattern. Using a fragment of the 3'UTR of the c-fos mRNA as a model, the interaction of CUG-BP, the human homolog of EDEN-BP - a protein previously implicated in regulated deadenylation in Xenopus oocytes - was shown to be associated with changes in PARN-mediated deadenylation patterns. Our results suggest that association of CUG-BP with 3'UTR sequences can modulate the activity of the PARN deadenylase in mammalian cell extracts.