scholarly journals The DNA Damage Response Signaling Cascade Regulates Proliferation of the Phytopathogenic Fungus Ustilago maydis in Planta

2011 ◽  
Vol 23 (4) ◽  
pp. 1654-1665 ◽  
Author(s):  
Carmen de Sena-Tomás ◽  
Alfonso Fernández-Álvarez ◽  
William K. Holloman ◽  
José Pérez-Martín
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ustilago Maydis ◽  
Phytopathogenic Fungus ◽  
Signaling Cascade ◽  
In Planta ◽  
Damage Response

scholarly journals HIV Vpr Modulates the Host DNA Damage Response at Two Independent Steps to Damage DNA and Repress Double-Strand DNA Break Repair

mBio ◽  
2020 ◽  
Vol 11 (4) ◽  
Author(s):  
Donna Li ◽  
Andrew Lopez ◽  
Carina Sandoval ◽  
Randilea Nichols Doyle ◽  
Oliver I. Fregoso
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Signaling Cascade ◽  
Human Pathogens ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
Damage Response ◽  
Hiv 1

ABSTRACT The DNA damage response (DDR) is a signaling cascade that is vital to ensuring the fidelity of the host genome in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and repression of the host DDR by diverse DNA and RNA viruses. Previous work has shown that HIV-1 is also capable of engaging the host DDR, primarily through the conserved accessory protein Vpr. However, the extent of this engagement has remained unclear. Here, we show that HIV-1 and HIV-2 Vpr directly induce DNA damage and stall DNA replication, leading to the activation of several markers of double- and single-strand DNA breaks. Despite causing damage and activating the DDR, we found that Vpr represses the repair of double-strand breaks (DSB) by inhibiting homologous recombination (HR) and nonhomologous end joining (NHEJ). Mutational analyses of Vpr revealed that DNA damage and DDR activation are independent from repression of HR and Vpr-mediated cell cycle arrest. Moreover, we show that repression of HR does not require cell cycle arrest but instead may precede this long-standing enigmatic Vpr phenotype. Together, our data uncover that Vpr globally modulates the host DDR at at least two independent steps, offering novel insight into the primary functions of lentiviral Vpr and the roles of the DNA damage response in lentiviral replication. IMPORTANCE The DNA damage response (DDR) is a signaling cascade that safeguards the genome from genotoxic agents, including human pathogens. However, the DDR has also been utilized by many pathogens, such as human immunodeficiency virus (HIV), to enhance infection. To properly treat HIV-positive individuals, we must understand how the virus usurps our own cellular processes. Here, we have found that an important yet poorly understood gene in HIV, Vpr, targets the DDR at two unique steps: it causes damage and activates DDR signaling, and it represses the ability of cells to repair this damage, which we hypothesize is central to the primary function of Vpr. In clarifying these important functions of Vpr, our work highlights the multiple ways human pathogens engage the DDR and further suggests that modulation of the DDR is a novel way to help in the fight against HIV.

scholarly journals HIV Vpr modulates the host DNA damage response at two independent steps to damage DNA and repress double-strand DNA break repair

2020 ◽  
Author(s):  
Donna Li ◽  
Andrew Lopez ◽  
Carina Sandoval ◽  
Randilea Nichols Doyle ◽  
Oliver I Fregoso
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Signaling Cascade ◽  
Human Pathogens ◽  
Dna Breaks ◽  
Cycle Arrest ◽  
Damage Response ◽  
Hiv 1

ABSTRACTThe DNA damage response (DDR) is a signaling cascade that is vital to ensuring the fidelity of the host genome in the presence of genotoxic stress. Growing evidence has emphasized the importance of both activation and repression of the host DDR by diverse DNA and RNA viruses. Previous work has shown that HIV-1 is also capable of engaging the host DDR, primarily through the conserved accessory protein Vpr. However, the extent of this engagement has remained unclear. Here we show that HIV-1 and HIV-2 Vpr directly induce DNA damage and stall DNA replication, leading to the activation of several markers of double- and single-strand DNA breaks. Despite causing damage and activating the DDR, we found that Vpr repress the repair of double-strand breaks (DSB) by inhibiting homologous recombination (HR) and non-homologous end joining (NHEJ). Mutational analyses of Vpr revealed that DNA damage and DDR activation are independent from repression of HR and Vpr-mediated cell-cycle arrest. Moreover, we show that repression of HR does not require cell-cycle arrest but instead may precede this long-standing enigmatic Vpr phenotype. Together, our data uncover that Vpr globally modulates the host DDR at at least two independent steps; offering novel insight into the primary functions of lentiviral Vpr and the roles of the DNA damage response in lentiviral replication.IMPORTANCEThe DNA damage response (DDR) is a signaling cascade that safeguards the genome from genotoxic agents, including human pathogens. However, the DDR has also been utilized by many pathogens, such as Human Immunodeficiency Virus (HIV), to enhance infection. To properly treat HIV positive individuals, we must understand how the virus usurps our own cellular processes. Here, we have found that an important yet poorly-understood gene in HIV, Vpr, targets the DDR at two unique steps: it causes damage and activates DDR signaling, and it represses the ability of cells to repair this damage, which we hypothesize is central to the primary function of Vpr. In clarifying these important functions of Vpr, our work highlights the multiple ways human pathogens engage the DDR, and further suggests that modulation of the DDR may be a novel way to help in the fight against HIV.

scholarly journals CSIG-25. MTAP LOSS COMPROMISES DNA DAMAGE RESPONSE IN GBM CELLS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi49-vi49
Author(s):  
Changzheng Du ◽  
Landon Hansen ◽  
Simranjit Singh ◽  
Kristen Roso ◽  
Paula Greer ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Ubiquitin Ligase ◽  
Cellular Response ◽  
E3 Ubiquitin Ligase ◽  
Genetic Alterations ◽  
Homozygous Deletion ◽  
Signaling Cascade ◽  
Dynamic Interactions ◽  
Damage Response

Abstract Homozygous deletion of methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic alterations in glioblastomas (GBMs), occurring in about half of all patients. Here, we demonstrated that MTAP loss compromises the proteostasis of genomic stability guardian, H2AX, via disrupting a signaling cascade of PRMT5-RNF168-SMURF2. We showed that PRMT5 sustains the expression of RNF168, an E3 ubiquitin ligase essential for cellular response to DNA damage. Suppression of PRMT5 function, as occurring in MTAP-null GBM cells, attenuates the expression of RNF168, which consequently leads to degradation of H2AX protein by a HECT-type E3 ubiquitin ligase, SMURF2. We revealed that RNF168 and SMURF2, serving as a stabilizer and destabilizer of H2AX respectively, functionally oppose each other via their dynamic interactions with H2AX. In supporting the important role of this PRMT5-RNF168-SMURF2 signaling cascade in controlling H2AX homeostasis, MTAP-null GBM cells display a compromised DNA damage response, highlighted by higher levels of DNA damage spontaneously or in response to genotoxic agents. Collectively, these results identify a novel signaling cascade that is essential to the DNA damage response, reveal the profound impact of MTAP loss on GBM cells, and suggest novel therapeutic opportunities.

2118-P: Regulation of Ataxia-Telangiectasia and Rad3-Related (ATR)–Dependent DNA Damage Response by Nitric Oxide in ß-Cells

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 2118-P
Author(s):  
CHAY TENG YEO ◽  
BRYNDON OLESON ◽  
JOHN A. CORBETT ◽  
JAMIE K. SCHNUCK
Keyword(s):  
Nitric Oxide ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
Damage Response
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