Nucleotide metabolism, oncogene-induced senescence and cancer

Aird, Katherine M.; Zhang, Rugang

doi:10.1016/j.canlet.2014.01.017

Cited by 108 publications

(90 citation statements)

References 103 publications

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“…Nucleotide homeostasis is closely related to human health and pathological conditions such as cancer development (Loffler et al 2005;Chabosseau et al 2011;Aird and Zhang 2015;Zauri et al 2015). Understanding how cells respond to and cope with related metabolic changes may also facilitate the development of therapeutic methods to treat these diseases.…”

Section: Discussionmentioning

confidence: 99%

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans

et al. 2016

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Animals alter their reproductive programs to accommodate changes in nutrient availability, yet the connections between known nutrient-sensing systems and reproductive programs are underexplored, and whether there is a mechanism that senses nucleotide levels to coordinate germline proliferation is unknown. We established a model system in which nucleotide metabolism is perturbed in both the nematode Caenorhabditis elegans (cytidine deaminases) and its food (Escherichia coli); when fed food with a low uridine/thymidine (U/T) level, germline proliferation is arrested. We provide evidence that this impact of U/T level on the germline is critically mediated by GLP-1/Notch and MPK-1/MAPK, known to regulate germline mitotic proliferation. This germline defect is suppressed by hyperactivation of glp-1 or disruption of genes downstream from glp-1 to promote meiosis but not by activation of the IIS or TORC1 pathways. Moreover, GLP-1 expression is post-transcriptionally modulated by U/T levels. Our results reveal a previously unknown nucleotide-sensing mechanism for controlling reproductivity.

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Section: Discussionmentioning

confidence: 99%

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans

et al. 2016

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“…Elevated cellular dNTP level is considered a biochemical marker of transformed/cancerous cells (42). Since nucleotide metabolism plays a role in transformation and tumor progression, inhibition of this pathway has long been considered a therapeutic strategy for cancer.…”

Section: Discussionmentioning

confidence: 99%

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

Ballana

Badía

Terradas

et al. 2014

Antimicrob Agents Chemother

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bSterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase recently recognized as an antiviral factor that acts by depleting dNTP availability for viral reverse transcriptase (RT). SAMHD1 restriction is counteracted by the human immunodeficiency virus type 2 (HIV-2) accessory protein Vpx, which targets SAMHD1 for proteosomal degradation, resulting in an increased availability of dNTPs and consequently enhanced viral replication. Nucleoside reverse transcriptase inhibitors (NRTI), one of the most common agents used in antiretroviral therapy, compete with intracellular dNTPs as the substrate for viral RT. Consequently, SAMHD1 activity may be influencing NRTI efficacy in inhibiting viral replication. Here, a panel of different RT inhibitors was analyzed for their different antiviral efficacy depending on SAMHD1. Antiviral potency was measured for all the inhibitors in transformed cell lines and primary monocytederived macrophages and CD4؉ T cells infected with HIV-1 with or without Vpx. No changes in sensitivity to non-NRTI or the integrase inhibitor raltegravir were observed, but for NRTI, sensitivity significantly changed only in the case of the thymidine analogs (AZT and d4T). The addition of exogenous thymidine mimicked the change in viral sensitivity observed after Vpx-mediated SAMHD1 degradation, pointing toward a differential effect of SAMHD1 activity on thymidine. Accordingly, sensitivity to AZT was also reduced in CD4؉ T cells infected with HIV-2 compared to infection with the HIV-2⌬Vpx strain. In conclusion, reduction of SAMHD1 levels significantly decreases HIV sensitivity to thymidine but not other nucleotide RT analog inhibitors in both macrophages and lymphocytes. Sterile alpha motif and histidine-aspartic domain-containing protein 1 (SAMHD1) is a recently identified human immunodeficiency virus type 1 (HIV-1) host restriction factor that limits retroviral replication at the reverse transcription stage of the viral life cycle (1-5). SAMHD1 functions as a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that regulates the intracellular pool of dNTPs (6). It restricts HIV-1 infection in immune cells of myeloid lineage and in quiescent CD4-positive T lymphocytes (1, 2, 4). SAMHD1 reduces cellular dNTP levels to concentrations below the threshold required for reverse transcription of the viral RNA genome into DNA (4, 5). SAMHD1 is counteracted by the retroviral Vpx protein that is encoded by simian immunodeficiency virus (SIV) and HIV-2, but this gene is lacking from the HIV-1 and feline immunodeficiency virus (FIV) genomes (7). However, and despite the lack of Vpx function, HIV-1 is still able to replicate in noncycling myeloid cells, albeit at low levels (7).Most current standard three-drug antiretroviral regimens involve RT inhibitors combined with a protease inhibitor. [EFV], and etravirine). NRTI are phosphorylated to their triphosphate form to act as competitive inhibitors of HIV RT. In contrast, NNRTI bind at...

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“…Following genome-wide replication stress, for example induced by oncogene activation, SLX4 may contribute to a sustained DNA damage response that is necessary to establish oncogene-induced senescence (OIS), which constitutes an early barrier to tumorigenesis (Bartek et al, 2012). Importantly, recent studies showed that nucleotide pool depletion induced by oncogene activation favors OIS and is also a tumor-suppressive mechanism (Aird and Zhang, 2014). Overall, our experiments using HU-induced nucleotide pool depletion suggest that loss of the SLX4 tumor suppressor might favor oncogenesis by helping precancerous or cancer cells escape OIS.…”

Section: Slx4 and Its Sumo-related Functions In Response Tomentioning

confidence: 99%

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

et al. 2015

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The SLX4 Fanconi anemia protein is a tumor suppressor that may act as a key regulator that engages the cell into specific genome maintenance pathways. Here, we show that the SLX4 complex is a SUMO E3 ligase that SUMOylates SLX4 itself and the XPF subunit of the DNA repair/recombination XPF-ERCC1 endonuclease. This SLX4-dependent activity is mediated by a remarkably specific interaction between SLX4 and the SUMO-charged E2 conjugating enzyme UBC9 and relies not only on newly identified SUMO-interacting motifs (SIMs) in SLX4 but also on its BTB domain. In contrast to its ubiquitin-binding UBZ4 motifs, SLX4 SIMs are dispensable for its DNA interstrand crosslink repair functions. Instead, while detrimental in response to global replication stress, the SUMO E3 ligase activity of the SLX4 complex is critical to prevent mitotic catastrophe following common fragile site expression.

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Nucleotide metabolism, oncogene-induced senescence and cancer

Cited by 108 publications

References 103 publications

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans

Nucleotide levels regulate germline proliferation through modulating GLP-1/Notch signaling in C. elegans

SAMHD1 Specifically Affects the Antiviral Potency of Thymidine Analog HIV Reverse Transcriptase Inhibitors

The SLX4 Complex Is a SUMO E3 Ligase that Impacts on Replication Stress Outcome and Genome Stability

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