CHK2 kinase in the DNA damage response and beyond

Zannini, Laura; Delia, Domenico; Buscemi, Giacomo

doi:10.1093/jmcb/mju045

Cited by 330 publications

(329 citation statements)

References 150 publications

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“…To achieve faithful chromosome segregation during cell division, the kinetochores of replicated chromatids need to attach to opposite poles of the mitotic spindle. Bipolar attachment of spindle microtubules to kinetochores is monitored by the spindle assembly checkpoint (SAC) 6 and dynamically regulated by phosphorylation and dephosphorylation to allow correction of improper attachment and stabilization of correct attachments (2)(3)(4). Key elements of this regulation are PLK1, Aurora B, and PP1/Sds22, whose opposing activities need to be tightly balanced (5)(6)(7).…”

mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr 232 ) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr 232 of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

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mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…ATM phosphorylates Chk2 at Threonine 68, and this Thr68-phosphorylated form of Chk2 localizes at sites of DNA breaks. 50,51 p53 becomes activated in response to different stressors, but in the case of DNA damage, phosphorylation of Serine 15 on p53 is required to permit local acetylation of histones and relaxation of chromatin. [52][53][54][55] To determine whether this signaling pathway associated with DNA damage is activated in latently infected cells, we analyzed the levels of phosphorylated forms of ATM at Ser1981, Chk2 at Thr68 and p53 at Ser15 (Fig.…”

Section: Signaling Of Dna Damage Is Activated In Cells Infected With mentioning

confidence: 99%

Deficiency in DNA damage response, a new characteristic of cells infected with latent HIV-1

et al. 2017

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Viruses can interact with host cell molecules responsible for the recognition and repair of DNA lesions, resulting in dysfunctional DNA damage response (DDR). Cells with inefficient DDR are more vulnerable to therapeutic approaches that target DDR, thereby raising DNA damage to a threshold that triggers apoptosis. Here, we demonstrate that 2 Jurkat-derived cell lines with incorporated silent HIV-1 provirus show increases in DDR signaling that responds to formation of double strand DNA breaks (DSBs). We found that phosphorylation of histone H2AX on Ser139 (gamma-H2AX), a biomarker of DSBs, and phosphorylation of ATM at Ser1981, Chk2 at Thr68, and p53 at Ser15, part of signaling pathways associated with DSBs, are elevated in these cells. These results indicate a DDR defect even though the virus is latent. DDR-inducing agents, specifically high doses of nucleoside RT inhibitors (NRTIs), caused greater increases in gamma-H2AX levels in latently infected cells. Additionally, latently infected cells are more susceptible to long-term exposure to G-quadruplex stabilizing agents, and this effect is enhanced when the agent is combined with an inhibitor targeting DNA-PK, which is crucial for DSB repair and telomere maintenance. Moreover, exposing these cells to the cancer drug etoposide resulted in formation of DSBs at a higher rate than in un-infected cells. Similar effects of etoposide were also observed in population of primary memory T cells infected with latent HIV-1. Sensitivity to these agents highlights a unique vulnerability of latently infected cells, a new feature that could potentially be used in developing therapies to eliminate HIV-1 reservoirs.

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“…A key downstream target of ATM is the effector checkpoint kinase Chk2 [12], which mediates transient arrest at multiple cell cycle phases to provide time for lesions to be repaired. Following its activation by ATM in response to DNA damage, Chk2 induces the phosphorylation of Cdc25A phosphatase and its subsequent degradation, preventing the dephosphorylation and activation of Cdk2, hence causing a G1/S checkpoint arrest.…”

Section: Introductionmentioning

confidence: 99%