miR-182-mediated downregulationo of BRCA1 impacts DNA repair and sensitivity to PARP inhibitors (Mol Cell, 2011, 41:210-220)

報告日期: 2011/04/22
報告時間: 15:10/16:00
報告學生: 裴武明皇 (英文報告)
講評老師: 黃溫雅

Full Text: http://basicmed.med.ncku.edu.tw/admin/up_img/0422-1.pdf

miR-182-Mediated Downregulation of BRCA1
impacts DNA repair and sensitivity to PARP inhibitors
Patryk Moskwa, Francesca M. Buffa, Yunfeng Pan, Rohit Panchakshari, Ponnari Gottipati, Ruth J. Muschel, John Beech, Ritu Kulshrestha, Kotb Abdelmohsen, David M. Weinstock, Myriam Gorospe, Adrian L. Harris, Thomas Helleday, and Dipanjan Chowdhury
Molecular Cell 2011, 41: 210–220
Speaker: Bui, Vo Minh Hoang
Commentator: Prof. Wen-Ya Huang
Date: 2011.04.22
Place: Room 602, College of Medicine
Basal-like breast tumors are subtypes of breast cancer and only represents about 15% of the invasive tumors. However, they accounts for 80-90% of the hereditary breast cancers, in which the expression of BRCA1 gene is decreased. BRCA1 is a human tumor suppressor gene producing protein to prevent cells from overgrowing and dividing too rapidly. Therefore, the decreased expression of the BRCA1 gene relates to poor prognosis of patients. The suppression of BRCA1 expression in these tumors is still unclear.
MicroRNAs (miRNAs) are small (18-24 nucleotides) non-coding RNAs, which play important roles in regulating the expression of target messenger RNAs (mRNAs). From their previous study, the authors showed that miRNAs downregulate double-strand break (DSB) repair factors and suppress DNA repair in terminally differentiated blood cells. So, the authors hypothesized that specific miRNAs may suppress BRCA1 expression in breast tumors.
To identify miRNAs targeting BRCA1 and other DSB factors.
By irradiating the hematopoietic cells and analysing their miRNA expression, the authors identified 5 miRNAs playing a role in DNA damage response. They focused on the miR-182. Then they used Argonaute/miR-182 complex to enrich selectively BRCA1 transcripts and luciferase reporter assay to show that miR-182 downregulates BRCA1 expression. They also showed that BRCA1 is a physiologically relevant target of miR-182 via evaluating the endogenous expression pattern of BRCA1 and miR-182. BRCA1 is known to control homology directed-DNA repair, but miR-182-mediated downregulation of BRCA1 was showed to block the DNA damage response.
More important, miR-182 was elucidated to target and to regulate the expression of BRCA1 during the cell cycle of breast tumor cell lines.
Finally, using the xenograft experiments, the authors clarified that miR-182 regulates the cellular response to PARP inhibitors of DNA repair.
The authors specifically addressed the role of miR-182 in directly targeting BRCA1, which is a human tumor suppressor gene and also the key player in DNA repair.
The authors also suggested that the PARP inhibition or other synthetic lethal strategies to BRCA may be effective in treating the sporadic tumors which overexpress miRNAs targeting BRCA proteins.
1.    Joosse SA, Brandwijk KIM, Mulder L, Wesseling J, Hannemann J, Nederlof PM. Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors. Genes, Chromosomes and Cancer. 2011; 50(2): 71-81.