HDAC1 and HDAC2 Integrate Checkpoint Kinase Phosphorylation and Cell Fate Through the Phosphatase-2A Subunit PR130

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Feb 24

PMID 29472538

Citations 37

Authors

Anja Goder

Claudia Emmerich

Teodora Nikolova

Nicole Kiweler

Maria Schreiber

Toni Kuhl

Diana Imhof

Markus Christmann

Thorsten Heinzel

Gunter Schneider

Oliver H Kramer

Affiliations

Soon will be listed here.

Abstract

Checkpoint kinases sense replicative stress to prevent DNA damage. Here we show that the histone deacetylases HDAC1/HDAC2 sustain the phosphorylation of the checkpoint kinases ATM, CHK1 and CHK2, activity of the cell cycle gatekeeper kinases WEE1 and CDK1, and induction of the tumour suppressor p53 in response to stalled DNA replication. Consequently, HDAC inhibition upon replicative stress promotes mitotic catastrophe. Mechanistically, HDAC1 and HDAC2 suppress the expression of PPP2R3A/PR130, a regulatory subunit of the trimeric serine/threonine phosphatase 2 (PP2A). Genetic elimination of PR130 reveals that PR130 promotes dephosphorylation of ATM by PP2A. Moreover, the ablation of PR130 slows G1/S phase transition and increases the levels of phosphorylated CHK1, replication protein A foci and DNA damage upon replicative stress. Accordingly, stressed PR130 null cells are very susceptible to HDAC inhibition, which abrogates the S phase checkpoint, induces apoptosis and reduces the homologous recombination protein RAD51. Thus, PR130 controls cell fate decisions upon replicative stress.

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References

Sorensen C, Hansen L, Dziegielewski J, Syljuasen R, Lundin C, Bartek J . The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol. 2005; 7(2):195-201. DOI: 10.1038/ncb1212. View

Kozlov S, Graham M, Jakob B, Tobias F, Kijas A, Tanuji M . Autophosphorylation and ATM activation: additional sites add to the complexity. J Biol Chem. 2010; 286(11):9107-19. PMC: 3059052. DOI: 10.1074/jbc.M110.204065. View

You Z, Bailis J, Johnson S, Dilworth S, Hunter T . Rapid activation of ATM on DNA flanking double-strand breaks. Nat Cell Biol. 2007; 9(11):1311-8. DOI: 10.1038/ncb1651. View

Toledo L, Altmeyer M, Rask M, Lukas C, Larsen D, Povlsen L . ATR prohibits replication catastrophe by preventing global exhaustion of RPA. Cell. 2013; 155(5):1088-103. DOI: 10.1016/j.cell.2013.10.043. View

Petermann E, Orta M, Issaeva N, Schultz N, Helleday T . Hydroxyurea-stalled replication forks become progressively inactivated and require two different RAD51-mediated pathways for restart and repair. Mol Cell. 2010; 37(4):492-502. PMC: 2958316. DOI: 10.1016/j.molcel.2010.01.021. View

Petermann E, Woodcock M, Helleday T . Chk1 promotes replication fork progression by controlling replication initiation. Proc Natl Acad Sci U S A. 2010; 107(37):16090-5. PMC: 2941317. DOI: 10.1073/pnas.1005031107. View

Brestovitsky A, Nebenzahl-Sharon K, Kechker P, Sharf R, Kleinberger T . The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response. PLoS Pathog. 2016; 12(2):e1005420. PMC: 4750969. DOI: 10.1371/journal.ppat.1005420. View

Dobbelstein M, Sorensen C . Exploiting replicative stress to treat cancer. Nat Rev Drug Discov. 2015; 14(6):405-23. DOI: 10.1038/nrd4553. View

Winter M, Moser M, Meunier D, Fischer C, Machat G, Mattes K . Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis. EMBO J. 2013; 32(24):3176-91. PMC: 3981143. DOI: 10.1038/emboj.2013.243. View

10.

McCluskey A, Keane M, Walkom C, Bowyer M, Sim A, Young D . The first two cantharidin analogues displaying PP1 selectivity. Bioorg Med Chem Lett. 2002; 12(3):391-3. DOI: 10.1016/s0960-894x(01)00777-6. View

11.

Crispin J, Apostolidis S, Finnell M, Tsokos G . Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2011; 108(30):12443-8. PMC: 3145691. DOI: 10.1073/pnas.1103915108. View

12.

Dunwell T, Hesson L, Pavlova T, Zabarovska V, Kashuba V, Catchpoole D . Epigenetic analysis of childhood acute lymphoblastic leukemia. Epigenetics. 2009; 4(3):185-93. DOI: 10.4161/epi.4.3.8752. View

13.

Schlacher K, Christ N, Siaud N, Egashira A, Wu H, Jasin M . Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell. 2011; 145(4):529-42. PMC: 3261725. DOI: 10.1016/j.cell.2011.03.041. View

14.

Smith J, Tho L, Xu N, Gillespie D . The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010; 108:73-112. DOI: 10.1016/B978-0-12-380888-2.00003-0. View

15.

Schafer C, Goder A, Beyer M, Kiweler N, Mahendrarajah N, Rauch A . Class I histone deacetylases regulate p53/NF-κB crosstalk in cancer cells. Cell Signal. 2016; 29:218-225. DOI: 10.1016/j.cellsig.2016.11.002. View

16.

Guzi T, Paruch K, Dwyer M, Labroli M, Shanahan F, Davis N . Targeting the replication checkpoint using SCH 900776, a potent and functionally selective CHK1 inhibitor identified via high content screening. Mol Cancer Ther. 2011; 10(4):591-602. DOI: 10.1158/1535-7163.MCT-10-0928. View

17.

Yamaguchi T, Cubizolles F, Zhang Y, Reichert N, Kohler H, Seiser C . Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 2010; 24(5):455-69. PMC: 2827841. DOI: 10.1101/gad.552310. View

18.

Heideman M, Wilting R, Yanover E, Velds A, de Jong J, Kerkhoven R . Dosage-dependent tumor suppression by histone deacetylases 1 and 2 through regulation of c-Myc collaborating genes and p53 function. Blood. 2013; 121(11):2038-50. PMC: 3596963. DOI: 10.1182/blood-2012-08-450916. View

19.

King C, Diaz H, Barnard D, Barda D, Clawson D, Blosser W . Characterization and preclinical development of LY2603618: a selective and potent Chk1 inhibitor. Invest New Drugs. 2013; 32(2):213-26. DOI: 10.1007/s10637-013-0036-7. View

20.

Yin S, Wang P, Yang L, Liu Y, Wang Y, Liu M . Wip1 suppresses ovarian cancer metastasis through the ATM/AKT/Snail mediated signaling. Oncotarget. 2016; 7(20):29359-70. PMC: 5045401. DOI: 10.18632/oncotarget.8833. View