scholarly journals Fine-tuning the DNA damage response: Protein Phosphatase 2A checks on CHK2

Cell Cycle ◽  
2010 ◽  
Vol 9 (5) ◽  
pp. 861-869 ◽  
Author(s):  
Marcus B. Smolka
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Fine Tuning ◽  
Damage Response ◽  
Phosphatase 2A

scholarly journals Mitosis-specific MPM-2 phosphorylation of DNA topoisomerase IIα is regulated directly by protein phosphatase 2A

2007 ◽  
Vol 403 (2) ◽  
pp. 235-242 ◽  
Author(s):  
Alexandre E. Escargueil ◽  
Annette K. Larsen
Keyword(s):  
Protein Phosphatase ◽  
Protein Phosphatase 2A ◽  
Fine Tuning ◽  
Classical Pathway ◽  
Complete Disappearance ◽  
Topoisomerase Iiα ◽  
Mitotic Entry ◽  
Mitotic Kinase ◽  
Short Term Exposure ◽  
Phosphatase 2A

Recent results suggest a role for topoIIα (topoisomerase IIα) in the fine-tuning of mitotic entry. Mitotic entry is accompanied by the formation of specific phosphoepitopes such as MPM-2 (mitotic protein monoclonal 2) that are believed to control mitotic processes. Surprisingly, the MPM-2 kinase of topoIIα was identified as protein kinase CK2, otherwise known as a constitutive interphase kinase. This suggested the existence of alternative pathways for the creation of mitotic phosphoepitopes, different from the classical pathway where the substrate is phosphorylated by a mitotic kinase. In the present paper, we report that topoIIα is co-localized with both CK2 and PP2A (protein phosphatase 2A) during interphase. Simultaneous incubation of purified topoIIα with CK2 and PP2A had minimal influence on the total phosphorylation levels of topoIIα, but resulted in complete disappearance of the MPM-2 phosphoepitope owing to opposite sequence preferences of CK2 and PP2A. Accordingly, short-term exposure of interphase cells to okadaic acid, a selective PP2A inhibitor, was accompanied by the specific appearance of the MPM-2 phosphoepitope on topoIIα. During early mitosis, PP2A was translocated from the nucleus, while CK2 remained in the nucleus until pro-metaphase thus permitting the formation of the MPM-2 phosphoepitope. These results underline the importance of protein phosphatases as an alternative way of creating cell-cycle-specific phosphoepitopes.

scholarly journals Phosphorylation of PLK3 Is Controlled by Protein Phosphatase 6

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1506 ◽  
Author(s):  
Cecilia Aquino Perez ◽  
Matous Palek ◽  
Lenka Stolarova ◽  
Patrick von Morgen ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Stress Response ◽  
Osmotic Stress ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Gene Editing ◽  
Kinase Activity ◽  
Cell Cycle Control ◽  
Damage Response ◽  
Transformed Cell Lines

Polo-like kinases play essential roles in cell cycle control and mitosis. In contrast to other members of this kinase family, PLK3 has been reported to be activated upon cellular stress including DNA damage, hypoxia and osmotic stress. Here we knocked out PLK3 in human non-transformed RPE cells using CRISPR/Cas9-mediated gene editing. Surprisingly, we find that loss of PLK3 does not impair stabilization of HIF1α after hypoxia, phosphorylation of the c-Jun after osmotic stress and dynamics of DNA damage response after exposure to ionizing radiation. Similarly, RNAi-mediated depletion of PLK3 did not impair stress response in human transformed cell lines. Exposure of cells to various forms of stress also did not affect kinase activity of purified EGFP-PLK3. We conclude that PLK3 is largely dispensable for stress response in human cells. Using mass spectrometry, we identify protein phosphatase 6 as a new interacting partner of PLK3. Polo box domain of PLK3 mediates the interaction with the PP6 complex. Finally, we find that PLK3 is phosphorylated at Thr219 in the T-loop and that PP6 constantly dephosphorylates this residue. However, in contrast to PLK1, phosphorylation of Thr219 does not upregulate enzymatic activity of PLK3, suggesting that activation of both kinases is regulated by distinct mechanisms.

scholarly journals Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

2021 ◽  
Vol 12 ◽  
Author(s):  
Clara Taffoni ◽  
Alizée Steer ◽  
Johanna Marines ◽  
Hanane Chamma ◽  
Isabelle K. Vila ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Dna Damage Response ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Fine Tuning ◽  
Innate Immune Activation ◽  
Damage Response

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

scholarly journals Protein Phosphatase 2A Antagonizes ATM and ATR in a Cdk2- and Cdc7-Independent DNA Damage Checkpoint

2006 ◽  
Vol 26 (5) ◽  
pp. 1997-2011 ◽  
Author(s):  
Paris Petersen ◽  
Danny M. Chou ◽  
Zhongsheng You ◽  
Tony Hunter ◽  
Johannes C. Walter ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Protein Phosphatase ◽  
Ataxia Telangiectasia ◽  
Protein Phosphatase 2A ◽  
Inhibitory Effect ◽  
Dna Damage Checkpoint ◽  
Free System ◽  
Phosphatase 2A ◽  
Initiation Of Dna Replication

ABSTRACT We previously used a soluble cell-free system derived from Xenopus eggs to investigate the role of protein phosphatase 2A (PP2A) in chromosomal DNA replication. We found that immunodepletion of PP2A or inhibition of PP2A by okadaic acid (OA) inhibits initiation of DNA replication by preventing loading of the initiation factor Cdc45 onto prereplication complexes. Evidence was provided that PP2A counteracts an inhibitory protein kinase that phosphorylates and inactivates a crucial Cdc45 loading factor. Here, we report that the inhibitory effect of OA is abolished by caffeine, an inhibitor of the checkpoint kinases ataxia-telangiectasia mutated protein (ATM) and ataxia-telangiectasia related protein (ATR) but not by depletion of ATM or ATR from the extract. Furthermore, we demonstrate that double-strand DNA breaks (DSBs) cause inhibition of Cdc45 loading and initiation of DNA replication and that caffeine, as well as immunodepletion of either ATM or ATR, abolishes this inhibition. Importantly, the DSB-induced inhibition of Cdc45 loading is prevented by addition of the catalytic subunit of PP2A to the extract. These data suggest that DSBs and OA prevent Cdc45 loading through different pathways, both of which involve PP2A, but only the DSB-induced checkpoint implicates ATM and ATR. The inhibitory effect of DSBs on Cdc45 loading does not result from downregulation of cyclin-dependent kinase 2 (Cdk2) or Cdc7 activity and is independent of Chk2. However, it is partially dependent on Chk1, which becomes phosphorylated in response to DSBs. These data suggest that PP2A counteracts ATM and ATR in a DNA damage checkpoint in Xenopus egg extracts.

scholarly journals PP2Cδ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer

2019 ◽  
Vol 5 (10) ◽  
pp. eaaw8417 ◽  
Author(s):  
Qun Li ◽  
Qiongyu Hao ◽  
Wei Cao ◽  
Jieqing Li ◽  
Ke Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Transcriptional Activity ◽  
Histological Grade ◽  
Anticancer Effect ◽  
Damage Response ◽  
Underlying Mechanisms ◽  
Mcf 7

Although nuclear type 2C protein phosphatase (PP2Cδ) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2Cδ levels with cancer development remain elusive. Here, we found that aberrant PP2Cδ activity decreases p53 acetylation and its transcriptional activity and suppresses doxorubicin-induced cell apoptosis. Mechanistically, we show that BRCA1 facilitates p300-mediated p53 acetylation by complexing with these two proteins and that S1423/1524 phosphorylation is indispensable for this regulatory process. PP2Cδ, via dephosphorylation of ATM, suppresses DNA damage–induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2Cδ levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2Cδ inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft–bearing nude mice. Together, our data indicate that PP2Cδ impairs p53 acetylation and DNA damage response by compromising BRCA1 function.

scholarly journals The protein phosphatase 1 regulator PNUTS is a new component of the DNA damage response

EMBO Reports ◽  
2010 ◽  
Vol 11 (11) ◽  
pp. 868-875 ◽  
Author(s):  
Helga B Landsverk ◽  
Felipe Mora‐Bermúdez ◽  
Ole J B Landsverk ◽  
Grete Hasvold ◽  
Soheil Naderi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Damage Response
Sign in / Sign up

Export Citation Format

Share Document