Startseite p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate
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p21Waf1 deficiency does not decrease DNA repair in E1A+cHa-Ras transformed cells by HDI sodium butyrate

  • Maria Igotti EMAIL logo , Olga Gnedina , Alisa Morshneva , Svetlana Svetlikova und Valery Pospelov
Veröffentlicht/Copyright: 24. Juli 2018

Abstract

This study aimed to explore a role of p21Waf1 in γH2AX foci formation and DNA repair as assessed by a Host-Cell Reactivation Assay in wild-type (p21Waf+/+) and p21Waf1-deficient E1A+Ras-transformed cells. p21Waf1+/+ cells have low γH2AX background compared to p21Waf1−/− cells. The treatment with histone deacetylase inhibitor (HDI) sodium butyrate (NaBut) causes to accumulation of γH2AX in p21Waf+/+ cells with little effect in p21Waf−/− cells. Moreover, NaBut inhibits DNA repair in wt cells but not in p21Waf1−/− cells. This could be explained by the weakening of GADD45 and PCNA proteins binding in NaBut-treated p21Waf1-expressing cells but not in p21Waf1−/− cells. We suggest that in wt-ERas cells NaBut activates both p21Waf1 expression and a release of p21Waf1 from the complexes with E1A that leads to suppression of DNA repair and promotes γH2AX persistency. The absence of p21Waf1 is by itself considered by the cell as stressful factor with formation of γH2AX. But the lack of p21Waf1 interferes with an inhibitory effect of NaBut to inhibit DNA repair and thereby to stop concomitant accumulation of harmful mutations. We conclude that p21Waf1 is directly involved in control of genome integrity and DNA repair acting through modulation of the components of the DNA repair machinery.

Award Identifier / Grant number: 14-50-00068

Funding statement: Authors thank Dr. Chuxia Deng for a kind of CDKN1A-knockout mice. This work was supported by grant of the Russian Science Foundation (RSF), Funder Id: 10.13039/501100006769, No. 14-50-00068 and in part by Funder Id: 10.13039/501100002674, the Program ‘Molecular and Cell Biology’ of the Russian Academy of Sciences.

References

Abramova, M.V., Pospelova, T.V., Nikulenkov, F.P., Hollander, C.M., Fornace, A.J., and Pospelov, V.A. (2006). G1/S arrest induced by histone deacetylase inhibitor sodium butyrate in E1A + Ras-transformed cells is mediated through down-regulation of E2F activity and stabilization of β-catenin. J. Biol. Chem. 281, 21040–21051.10.1074/jbc.M511059200Suche in Google Scholar PubMed

Abramova, M.V., Zatulovskiy, E.A., Svetlikova, S.B., and Pospelov, V.A. (2010). HDAC inhibitor-induced activation of NF-κB prevents apoptotic response of E1A+Ras-transformed cells to proapoptotic stimuli. Int. J. Biochem. Cell Biol. 42, 1847–1855.10.1016/j.biocel.2010.08.001Suche in Google Scholar PubMed

Abramova, M.V., Svetlikova, S.B., Kukushkin, A.N., Aksenov, N.D., Pospelova, T.V., and Pospelov, V.A. (2011). HDAC inhibitor sodium butyrate sensitizes E1A+Ras-transformed cells to DNA damaging agents by facilitating formation and persistence of γH2AX foci. Cancer Biol. Ther. 12, 1069–1077.10.4161/cbt.12.12.18365Suche in Google Scholar PubMed

Bandara, L.R. and La Thangue, N.B. (1991). Adenovirus E1a prevents the retinoblastoma gene product from complexing with a cellular transcription factor. Nature 351, 494–497.10.1038/351494a0Suche in Google Scholar PubMed

Bulavin, D.V., Tararova, N.D., Aksenov, N.D., Pospelov, V.A., and Pospelova, T.V. (1999). Deregulation of p53/p21(Cip1/Waf1) pathway contributes to polyploidy and apoptosis of E1A + cHa-ras transformed cells after γ-irradiation. Oncogene 18, 5611–5619.10.1038/sj.onc.1202945Suche in Google Scholar PubMed

Carrier, F., Georgel, P.T., Pourquier, P., Blake, M., Kontny, H.U., Antinore, M.J., Gariboldi, M., Myers, T.G., Weinstein, J.N., Pommier, Y., et al. (1999). Gadd45, a p53-responsive stress protein, modifies DNA accessibility on damaged chromatin. Mol. Cell. Biol. 19, 1673–1685.10.1128/MCB.19.3.1673Suche in Google Scholar PubMed PubMed Central

Chattopadhyay, D., Ghosh, M.K., Mal, A., and Harter, M.L. (2001). Inactivation of p21 by E1A leads to the induction of apoptosis in DNA-damaged cells. J. Virol. 75, 9844–9856.10.1128/JVI.75.20.9844-9856.2001Suche in Google Scholar PubMed PubMed Central

Chen, I.T., Smith, M.L., O’Connor, P.M., and Fornace, A.J. (1995). Direct interaction of Gadd45 with PCNA and evidence for competitive interaction of Gadd45 and p21Waf1/Cip1 with PCNA. Oncogene 11, 1931–1937.Suche in Google Scholar

Chopin, V., Toillon, R.-A., Jouy, N., and Le Bourhis, X. (2004). P21(WAF1/CIP1) is dispensable for G1 arrest, but indispensable for apoptosis induced by sodium butyrate in MCF7 breast cancer cells. Oncogene 8, 21–29.10.1038/sj.onc.1207020Suche in Google Scholar PubMed

Fotedar, R., Bendjennat, M., and Fotedar, A. (2004). Role of p21WAF1 in the cellular response to UV. Cell Cycle 3, 134–137.10.4161/cc.3.2.658Suche in Google Scholar PubMed

Fulda, S. and Debatin, K.-M. (2004). Sensitization for tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by the chemopreventive agent resveratrol. Cancer Res. 64, 337–346.10.1158/0008-5472.CAN-03-1656Suche in Google Scholar PubMed

Igotti Abramova, M.V., Pojidaeva, A.K., Filippova, E.A., Gnedina, O.O., Svetlikova, S.B., and Pospelov, V.A. (2014). HDAC inhibitors induce apoptosis but not cellular senescence in Gadd45α-deficient E1A+Ras cells. Int. J. Biochem. Cell Biol. 51, 102–110.10.1016/j.biocel.2014.03.031Suche in Google Scholar PubMed

Jakob, B., Scholz, M., and Taucher-Scholz, G. (2002). Characterization of CDKN1A (p21) binding to sites of heavy-ion-induced damage: colocalization with proteins involved in DNA repair. Int. J. Radiat. Biol. 78, 75–88.10.1080/09553000110090007Suche in Google Scholar PubMed

Kearsey, J.M., Coates, P.J., Prescott, A.R., Warbrick, E., and Hall, P.A. (1995). Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Oncogene 11, 1675–1683.Suche in Google Scholar

Keblusek, P., Dorsman, J.C., Teunisse, A.F., Teunissen, H., van der Eb, A.J., and Zantema, A. (1999). The adenoviral E1A oncoproteins interfere with the growth-inhibiting effect of the cdk-inhibitor p21(CIP1/WAF1). J. Gen. Virol. 80, 381–390.10.1099/0022-1317-80-2-381Suche in Google Scholar PubMed

Kochetkova, E.Y., Blinova, G.I., Bystrova, O.A., Martynova, M.G., Pospelov, V.A., and Pospelova, T.V. (2017). Targeted elimination of senescent Ras-transformed cells by suppression of MEK/ERK pathway. Aging 9, 2352–2375.10.18632/aging.101325Suche in Google Scholar PubMed PubMed Central

Koike, M., Yutoku, Y., and Koike, A. (2011). Accumulation of p21 proteins at DNA damage sites independent of p53 and core NHEJ factors following irradiation. Biochem. Biophys. Res. Commun. 412, 39–43.10.1016/j.bbrc.2011.07.032Suche in Google Scholar PubMed

Mauro, M., Rego, M.A., Boisvert, R.A., Esashi, F., Cavallo, F., Jasin, M., and Howlett, N.G. (2012). p21 promotes error-free replication-coupled DNA double-strand break repair. Nucleic Acids Res. 40, 8348–8360.10.1093/nar/gks612Suche in Google Scholar PubMed PubMed Central

McDonald, E.R., Wu, G.S., Waldman, T., and El-Deiry, W.S. (1996). Repair defect in p21 WAF1/CIP1−/− human cancer cells. Cancer Res. 56, 2250–2255.Suche in Google Scholar

Moldovan, G.-L., Pfander, B., and Jentsch, S. (2007). PCNA, the maestro of the replication fork. Cell 129, 665–679.10.1016/j.cell.2007.05.003Suche in Google Scholar PubMed

Pehrson, J.R. and Fuji, R.N. (1998). Evolutionary conservation of histone macroH2A subtypes and domains. Nucleic Acids Res. 26, 2837–2842.10.1093/nar/26.12.2837Suche in Google Scholar PubMed PubMed Central

Riches, L.C., Lynch, A.M., and Gooderham, N.J. (2008). Early events in the mammalian response to DNA double-strand breaks. Mutagenesis 23, 331–339.10.1093/mutage/gen039Suche in Google Scholar PubMed

Romanov, V.S., Abramova, M.V., Svetlikova, S.B., Bykova, T.V., Zubova, S.G., Aksenov, N.D., Fornace, A.J., Pospelova, T.V., and Pospelov, V.A. (2010). p21 Waf1 is required for cellular senescence but not for cell cycle arrest induced by the HDAC inhibitor sodium butyrate. Cell Cycle 9, 3945–3955.10.4161/cc.9.19.13160Suche in Google Scholar PubMed

Schrump, D.S. (2009). Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin. Cancer Res. 15, 3947–3957.10.1158/1078-0432.CCR-08-2787Suche in Google Scholar PubMed PubMed Central

Sheikh, M.S., Chen, Y.Q., Smith, M.L., and Fornace, A.J. (1997). Role of p21Waf1/Cip1/Sdi1 in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene 14, 1875–1882.10.1038/sj.onc.1201004Suche in Google Scholar PubMed

Smith, M.L., Chen, I.T., Zhan, Q., Bae, I., Chen, C.Y., Gilmer, T.M., Kastan, M.B., O’Connor, P.M., and Fornace, A.J. (1994). Interaction of the p53-regulated protein Gadd45 with proliferating cell nuclear antigen. Science 266, 1376–1380.10.1126/science.7973727Suche in Google Scholar PubMed

Smith, M.L., Ford, J.M., Hollander, M.C., Bortnick, R.A., Amundson, S.A., Seo, Y.R., Deng, C.X., Hanawalt, P.C., and Fornace, A.J. (2000). p53-mediated DNA repair responses to UV radiation: studies of mouse cells lacking p53, p21, and/or gadd45 genes. Mol. Cell. Biol. 20, 3705–3714.10.1128/MCB.20.10.3705-3714.2000Suche in Google Scholar PubMed PubMed Central

Wang, X.M., Li, J., and Evers, B.M. (1999). Inhibition of proliferation, invasion and adhesion of liver cancer cells by 5-azacytidine and butyrate. Anticancer Res. 19, 2901–2906.Suche in Google Scholar

Wiese, C., Rudolph, J.H., Jakob, B., Fink, D., Tobias, F., Blattner, C., and Taucher-Scholz, G. (2012). PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation. DNA Repair 11, 511–521.10.1016/j.dnarep.2012.02.006Suche in Google Scholar PubMed

Yata, K. and Esashi, F. (2009). Dual role of CDKs in DNA repair: to be, or not to be. DNA Repair 8, 6–18.10.1016/j.dnarep.2008.09.002Suche in Google Scholar PubMed


Supplementary Material:

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0249).


Received: 2018-05-11
Accepted: 2018-07-09
Published Online: 2018-07-24
Published in Print: 2018-10-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

Heruntergeladen am 6.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0249/pdf
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