Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol

Department of Molecular Biology, CH-1205 Geneva, Switzerland.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 03/2010; 11(3):220-8. DOI: 10.1038/nrm2858
Source: PubMed


Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

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    • "DNA damage initiates a tightly coordinated signaling response to maintain genomic integrity, and defects in the DDR often lead to increased incorporation of mutations into newly synthesized DNA, the accumulation of chromosomal instability and tumor development (Abbas and Dutta, 2009; Negrini et al., 2010). The DDR is primarily initiated by activation of related kinases ATM, ATR, and DNA-dependent protein kinase (DNA-PK) and by members of the poly (ADP-ribose) polymerase (PARP) family (Ciccia and Elledge, 2010). "

    Molecules and Cells 09/2015; 38(9):750-758. DOI:10.14348/molcells.2015.0167 · 2.09 Impact Factor
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    • "In addition to the ATM-mediated DNA damage response, it has been found that upregulation of oncogenic c-Myc induces ROS and promotes DNA damage (Vafa et al. 2002). Moreover, c-Myc upregulation suppresses repair of DNA DSB (Li et al. 2012) that can lead to oncogene-induced genetic instability, which is an evolving hallmark of cancer (Negrini et al. 2010). In parallel, deregulated c-Myc can also debilitate p53-mediated cell cycle arrest (Vafa et al. 2002) and promote proliferative signaling, which is a hallmark of cancer (Hanahan and Weinberg 2011). "
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    ABSTRACT: Humans are exposed to low dose Bisphenol A (BPA) through plastic consumer products and dental sealants with BPA. While a number of studies have investigated the mammary gland effects after high-dose BPA exposure, the study findings differ. Furthermore, there has been a lack of mechanistic studies. The objective of this study is to investigate the effect and the mechanism of low dose BPA in mammary gland cells. We evaluated DNA damage following BPA exposure using the comet assay and immunofluorescence staining, and used cell counting and three-dimensional cultures to evaluate effects on proliferation. We examined the expressions of markers of DNA damage and cell-cycle regulators by immunoblotting and performed siRNA-mediated gene silencing to determine the role of c-Myc in regulating BPA's effects. Low-dose BPA significantly promoted DNA damage, upregulated c-Myc and other cell-cycle regulatory proteins, and induced proliferation in parallel in estrogen receptor-α (ERα)-negative mammary cells. Silencing c-Myc diminished these BPA-induced cellular events, suggesting that c-Myc is essential for regulating effects of BPA on DNA damage and proliferation in mammary cells. Low-dose BPA exerted c-Myc-dependent genotoxic and mitogenic effects on ERα-negative mammary cells. These findings provide significant evidence of adverse effects of low-dose BPA on mammary cells.
    Environmental Health Perspectives 05/2015; DOI:10.1289/ehp.1409199 · 7.98 Impact Factor
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    • "Inability to repair DSBs leads to DNA fragmentation and cell death. Unfaithful repair results in genetic instability (GIN) where cells may survive but chromosomes become rearranged, and genetic material mutated, duplicated, or deleted (Negrini et al., 2010). GIN is a defining characteristic of cancer (Schmitt et al., 2012) promoting initiation and somatic evolution, in turn, linking to disease progression and therapy resistance. "
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    ABSTRACT: Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1's cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(12). DOI:10.1016/j.celrep.2015.02.059 · 8.36 Impact Factor
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