Mueller AC, Sun D, Dutta AThe miR-99 family regulates the DNA damage response through its target SNF2H. Oncogene 32(9): 1164-1172

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, USA.
Oncogene (Impact Factor: 8.46). 04/2012; 32(9). DOI: 10.1038/onc.2012.131
Source: PubMed


Chromatin remodeling factors are becoming known as crucial facilitators of recruitment of repair proteins to sites of DNA damage. Multiple chromatin remodeling protein complexes are now known to be required for efficient double strand break repair. In a screen for microRNAs (miRNAs) that modulate the DNA damage response, we discovered that expression of the miR-99 family of miRNAs correlates with radiation sensitivity. These miRNAs were also transiently induced following radiation. The miRNAs target the SWI/SNF chromatin remodeling factor SNF2H/SMARCA5, a component of the ACF1 complex. We found that by reducing levels of SNF2H, miR-99a and miR-100 reduced BRCA1 localization to sites of DNA damage. Introduction of the miR-99 family of miRNAs into cells reduced the rate and overall efficiency of repair by both homologous recombination and non-homologous end joining. Finally, induction of the miR-99 family following radiation prevents an increase in SNF2H expression and reduces the recruitment of BRCA1 to the sites of DNA damage following a second dose of radiation, reducing the efficiency of repair after multiple rounds of radiation, as used in fractionated radiotherapy.Oncogene advance online publication, 23 April 2012; doi:10.1038/onc.2012.131.

Download full-text


Available from: Adam Christopher Mueller, Nov 06, 2014
  • Source
    • "(For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) 17 miR-421, miR-101 and miR-100, which then activate cell cycle checkpoint [36] [37] [38] [39]. The down-regulation of miR-106b regulates p21-dependent G2/M cell cycle arrest [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, which if unrepaired or repaired incorrectly can cause cell death or genome instability that may lead to cancer. To counteract these adverse consequences, eukaryotes have evolved a highly orchestrated mechanism to repair DSBs, namely DNA-damage-response (DDR). DDR, as defined specifically in relation to DSBs, consists of multi-layered regulatory modes including DNA damage sensors, transducers and effectors, through which DSBs are sensed and then repaired via DNAprotein interactions. Unexpectedly, recent studies have revealed a direct role of RNA in the repair of DSBs, including DSB-induced small RNA (diRNA)-directed and RNA-templated DNA repair. Here, we summarize the recent discoveries of RNA-mediated regulation of DSB repair and discuss the potential impact of these novel RNA components of the DSB repair pathway on genomic stability and plasticity. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · May 2015 · DNA repair
  • Source
    • "Their analysis revealed 37 downregulated and 14 upregulated miRs in PCa specimens. Among downregulated microRNAs miR-16, miR-99, and let-7 family are well known tumor-suppressor genes [39] [40] [41] [42]. Interestingly , reduced levels of miR-205, miR-100, and miR-30 family were observed only in hormone-refractory specimens suggesting a hypothetical prognostic role for CRPC prediction. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PCa) is one of the leading causes of cancer-related death in men. Despite considerable advances in prostate cancer early detection and clinical management, validation of new biomarkers able to predict the natural history of tumor progression is still necessary in order to reduce overtreatment and to guide therapeutic decisions. MicroRNAs are endogenous noncoding RNAs which offer a fast fine-tuning and energy-saving mechanism for posttranscriptional control of protein expression. Growing evidence indicate that these RNAs are able to regulate basic cell functions and their aberrant expression has been significantly correlated with cancer development. Therefore, detection of microRNAs in tumor tissues and body fluids represents a new tool for early diagnosis and patient prognosis prediction. In this review, we summarize current knowledge about microRNA deregulation in prostate cancer mainly focusing on the different clinical aspects of the disease. We also highlight the potential roles of microRNAs in PCa management, while also discussing several current challenges and needed future research.
    Full-text · Article · Sep 2014 · BioMed Research International
  • Source
    • "While a vast amount of current research focuses on miRNAs in combination with chemotherapy, a small body of studies examines irradiation treatments in conjunction with miRNA treatment. The alteration of miRNAs involved in DNA damage repair due to radiation would allow for cancer cells to resist radiation treatment [131–133]. To this extent, Huang et al. focused on RAD51 and its paralog RAD51D, two proteins involved in homologous recombination mediated double strand break repair. "
    [Show abstract] [Hide abstract]
    ABSTRACT: First discovered in 1993, microRNAs (miRNAs) have been one of the hottest research areas over the past two decades. Oftentimes, miRNAs levels are found to be dysregulated in cancer patients. The potential use of miRNAs in cancer therapies is an emerging and promising field, with research finding miRNAs to play a role in cancer initiation, tumor growth, and metastasis. Therefore, miRNAs could become an integral part from cancer diagnosis to treatment in future. This review aims to examine current novel research work on the potential roles of miRNAs in cancer therapies, while also discussing several current challenges and needed future research.
    Full-text · Article · Jul 2014 · BioMed Research International
Show more