2014
DOI: 10.1128/jvi.01412-14
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The ATR Signaling Pathway Is Disabled during Infection with the Parvovirus Minute Virus of Mice

Abstract: The ATR kinase has essential functions in maintenance of genome integrity in response to replication stress. ATR is recruited to RPA-coated single-stranded DNA at DNA damage sites via its interacting partner, ATRIP, which binds to the large subunit of RPA. ATR activation typically leads to activation of the Chk1 kinase among other substrates. We show here that, together with a number of other DNA repair proteins, both ATR and its associated protein, ATRIP, were recruited to viral nuclear replication compartmen… Show more

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Cited by 14 publications
(33 citation statements)
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“…This timing suggests that it may well be a response to replicating nuclear DNA. and its induction should result in changes in the way the infected cell responds to experimental stimuli, as recently reported, for example, for IL-6 expression in response to poly I-C stimulation (Mattei et al 2013), or Chk1 activation in response hydroxyurea treatment (Adeyemi and Pintel, 2014a). Overall, plausible explanations include failure to evade aspects of the induced DNA damage response (Adeyemi et al, 2010; Ruiz et al, 2011), failure to subvert the cell cycle (Adeyemi and Pintel, 2014b: Cotmore and Tattersall, 2013), or the induction of an innate antiviral response to replicating viral DNA, which NS2P, and by extension NP1, would be able to suppress.…”
Section: Discussionmentioning
confidence: 78%
“…This timing suggests that it may well be a response to replicating nuclear DNA. and its induction should result in changes in the way the infected cell responds to experimental stimuli, as recently reported, for example, for IL-6 expression in response to poly I-C stimulation (Mattei et al 2013), or Chk1 activation in response hydroxyurea treatment (Adeyemi and Pintel, 2014a). Overall, plausible explanations include failure to evade aspects of the induced DNA damage response (Adeyemi et al, 2010; Ruiz et al, 2011), failure to subvert the cell cycle (Adeyemi and Pintel, 2014b: Cotmore and Tattersall, 2013), or the induction of an innate antiviral response to replicating viral DNA, which NS2P, and by extension NP1, would be able to suppress.…”
Section: Discussionmentioning
confidence: 78%
“…The ATR-Chk1 pathway is important for the stabilization of stalled replication forks. Several DNA viruses, including herpesvirus, adenovirus, and parvovirus, can disable ATR signaling (27,45,46). During HSV-1 infection, viral replication proteins and ATR/ATRIP are recruited to viral replication forks and, with ATR-Chk1 pathway inhibition, may lead to replication fork collapse.…”
Section: Discussionmentioning
confidence: 99%
“…During host cell infection, MVM induces a vigorous DDR in murine cells in which p53 is continually activated. Surprisingly, however, p21 WAF1/Cip1 (hereafter referred to as p21) and CHK1 (as discussed more fully below), major effectors typically associated with S-phase and G2-phase cell cycle arrest in response to diverse DNA damage stimuli, remain depleted or are inactivated, respectively [ 27 , 28 , 38 ]. Cycling cells typically reversibly down regulate p21 upon S-phase entry or in response to DNA double strand breaks, which is then restored to basal levels upon S-phase exit.…”
Section: Mvm-induced Perturbations Of the Cell Cyclementioning
confidence: 99%
“…Depleted levels of p21 can be restored by treating infected cells with the proteasome inhibitor MG132, suggesting that p21 degradation during MVM infection is performed by the proteasomal machinery. Interestingly, however, whereas ATR activity modulates p21 degradation in response to various DDR-inducing agents (as described more fully below), the activation of ATR and its substrate CHK1 is reduced during MVM infection, consistent with the independence of p21 signaling from this pathway [ 28 ]. Similar to the case described above for cyclin B1 expression, while MVM infection leads to a loss of p21, the ectopic expression of NS1 results in increased p21 levels [ 39 ].…”
Section: Regulation Of P21 By Mvm Infectionmentioning
confidence: 99%
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