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.

    • "In nearly all tumor cell types, the degree of replication stress is enhanced. Activated oncogenes drive cell proliferation by interfering with regulatory pathways of cell cycle progression control, leading to replication stress and replication associated DNA damage[135]. Hence, pathways that promote replication stress tolerance are obvious targets for development of new cancer therapies. "
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    ABSTRACT: A dividing cell has to duplicate its DNA precisely once during the cell cycle to preserve genome integrity avoiding the accumulation of genetic aberrations that promote diseases such as cancer. A large number of endogenous impacts can challenge DNA replication and cells harbor a battery of pathways to promote genome integrity during DNA replication. This includes suppressing new replication origin firing, stabilization of replicating forks, and the safe restart of forks to prevent any loss of genetic information. Here, we describe mechanisms by which oncogenes can interfere with DNA replication thereby causing DNA replication stress and genome instability. Further, we describe cellular and systemic responses to these insults with a focus on DNA replication restart pathways. Finally, we discuss the therapeutic potential of exploiting intrinsic replicative stress in cancer cells for targeted therapy.
    No preview · Article · Jan 2016 · Seminars in Cancer Biology
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    • "However, heightened genomic instability can also activate DNA damage-associated checkpoints, which can lead to apoptosis or cellular senescence. Cancer cells continuously tread a fine balance between cell death and survival in response to DNA damage (Negrini et al., 2010). Chronic myeloproliferative neoplasms (MPNs) encompass a spectrum of clonal hematological disorders with an inherent tendency to transform into a more aggressive disease in the form of acute myeloid leukemia (AML). "
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    ABSTRACT: JAK2V617F is the most common oncogenic lesion in patients with myeloproliferative neoplasms (MPNs). Despite the ability of JAK2V617F to instigate DNA damage in vitro, MPNs are nevertheless characterized by genomic stability. In this study, we address this paradox by identifying the DNA helicase RECQL5 as a suppressor of genomic instability in MPNs. We report increased RECQL5 expression in JAK2V617F-expressing cells and demonstrate that RECQL5 is required to counteract JAK2V617F-induced replication stress. Moreover, RECQL5 depletion sensitizes JAK2V617F mutant cells to hydroxyurea (HU), a pharmacological inducer of replication stress and the most common treatment for MPNs. Using single-fiber chromosome combing, we show that RECQL5 depletion in JAK2V617F mutant cells impairs replication dynamics following HU treatment, resulting in increased double-stranded breaks and apoptosis. Cumulatively, these findings identify RECQL5 as a critical regulator of genome stability in MPNs and demonstrate that replication stress-associated cytotoxicity can be amplified specifically in JAK2V617F mutant cells through RECQL5-targeted synthetic lethality.
    Full-text · Article · Dec 2015 · Cell Reports
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    • "Recent study of transcripts from bone marrow cells revealed that FA patients have deficiencies in mitochondrial, redox and DNA repair pathways [41] [42]. Another DNA-repair deficient disease is Ataxia Telangiectasia (AT) that is caused by muta‐ tions on the ATM gene [43]. Recently, it was reported that lack of ATM causes reduced mitochondrial DNA integrity and mitochondrial dysfunction [44]. "
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    ABSTRACT: In this chapter, we will focus on and discuss transcriptional mechanisms that regulate both DNA repair and mitochondrial functions. Not only DNA repair systems, but also several metabolic enzyme reactions that depend on an inner cellular NAD+/NADH ratio, including TCA (Citrate/Krebs) cycle and poly (ADP-ribosyl)ation, are thought to be dys-regulated in cancer or tumor cells. We therefore, propose a novel cancer therapy by introducing GGAA-motif binding TFs or their expression vectors, activating both DNA repair and mitochondrial functions.
    Full-text · Chapter · Nov 2015
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