Embryonic Stem Cells Lacking the Epigenetic Regulator Cfp1 Are Hypersensitive to DNA-damaging Agents and Exhibit Decreased Ape1/Ref-1 Protein Expression and Endonuclease Activity

Overview

Journal DNA Repair (Amst)

Publisher Elsevier

Specialties Biochemistry
Molecular Biology

Date 2009 Oct 20

PMID 19836314

Citations 1

Authors

Courtney M Tate

Melissa L Fishel

Julianne L Holleran

Merrill J Egorin

David G Skalnik

Affiliations

Soon will be listed here.

Abstract

Modulation of chromatin structure plays an important role in the recruitment and function of DNA repair proteins. CXXC finger protein 1 (Cfp1), encoded by the CXXC1 gene, is essential for mammalian development and is an important regulator of chromatin structure. Murine embryonic stem (ES) cells lacking Cfp1 (CXXC1(-/-)) are viable but demonstrate a dramatic decrease in cytosine methylation, altered histone methylation, and an inability to differentiate. We find that ES cells lacking Cfp1 are hypersensitive to a variety of DNA-damaging agents. In addition, CXXC1(-/-) ES cells accumulate more DNA damage and exhibit decreased protein expression and endonuclease activity of AP endonuclease (Ape1/Ref-1), an enzyme involved in DNA base excision repair. Expression in CXXC1(-/-) ES cells of either the amino half of Cfp1 (amino acids 1-367) or the carboxyl half of Cfp1 (amino acids 361-656) restores normal Ape1/Ref-1 protein expression and rescues the hypersensitivity to DNA-damaging agents, demonstrating that Cfp1 contains redundant functional domains. Furthermore, retention of either the DNA-binding activity of Cfp1 or interaction with the Setd1A and Setd1B histone H3-Lys4 methyltransferase complexes is required to restore normal sensitivity of CXXC1(-/-) ES cells to DNA-damaging agents. These results implicate Cfp1 as a regulator of DNA repair processes.

Citing Articles

Recent therapeutic strategies for spinal cord injury treatment: possible role of stem cells.

Garbossa D, Boido M, Fontanella M, Fronda C, Ducati A, Vercelli A Neurosurg Rev. 2012; 35(3):293-311.

PMID: 22539011 DOI: 10.1007/s10143-012-0385-2.

References

Kim M, Baek J, Chakravarty D, Sidransky D, Carrier F . Sensitization to UV-induced apoptosis by the histone deacetylase inhibitor trichostatin A (TSA). Exp Cell Res. 2005; 306(1):94-102. DOI: 10.1016/j.yexcr.2005.02.013. View

Abal M, Andreu J, Barasoain I . Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets. 2003; 3(3):193-203. DOI: 10.2174/1568009033481967. View

Mitra S, Izumi T, Boldogh I, Bhakat K, Chattopadhyay R, Szczesny B . Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein. DNA Repair (Amst). 2006; 6(4):461-9. DOI: 10.1016/j.dnarep.2006.10.010. View

Jiang Y, Guo C, Vasko M, Kelley M . Implications of apurinic/apyrimidinic endonuclease in reactive oxygen signaling response after cisplatin treatment of dorsal root ganglion neurons. Cancer Res. 2008; 68(15):6425-34. PMC: 2591093. DOI: 10.1158/0008-5472.CAN-08-1173. View

Peterson C, Laniel M . Histones and histone modifications. Curr Biol. 2004; 14(14):R546-51. DOI: 10.1016/j.cub.2004.07.007. View

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

Jones P, Baylin S . The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002; 3(6):415-28. DOI: 10.1038/nrg816. View

Ozaki K, Kishikawa F, Tanaka M, Sakamoto T, Tanimura S, Kohno M . Histone deacetylase inhibitors enhance the chemosensitivity of tumor cells with cross-resistance to a wide range of DNA-damaging drugs. Cancer Sci. 2008; 99(2):376-84. PMC: 11158297. DOI: 10.1111/j.1349-7006.2007.00669.x. View

Op het Veld C, Jansen J, Zdzienicka M, Vrieling H, van Zeeland A . Methyl methanesulfonate-induced hprt mutation spectra in the Chinese hamster cell line CHO9 and its xrcc1-deficient derivative EM-C11. Mutat Res. 1998; 398(1-2):83-92. DOI: 10.1016/s0027-5107(97)00243-1. View

10.

Karagiannis T, Harikrishnan K, Kn H, El-Osta A . Disparity of histone deacetylase inhibition on repair of radiation-induced DNA damage on euchromatin and constitutive heterochromatin compartments. Oncogene. 2007; 26(27):3963-71. DOI: 10.1038/sj.onc.1210174. View

11.

Bapat A, Fishel M, Kelley M . Going ape as an approach to cancer therapeutics. Antioxid Redox Signal. 2008; 11(3):651-68. PMC: 2787666. DOI: 10.1089/ars.2008.2218. View

12.

Rabik C, Fishel M, Holleran J, Kasza K, Kelley M, Egorin M . Enhancement of cisplatin [cis-diammine dichloroplatinum (II)] cytotoxicity by O6-benzylguanine involves endoplasmic reticulum stress. J Pharmacol Exp Ther. 2008; 327(2):442-52. PMC: 3785988. DOI: 10.1124/jpet.108.141291. View

13.

Balaghi M, Wagner C . DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun. 1993; 193(3):1184-90. DOI: 10.1006/bbrc.1993.1750. View

14.

Ataian Y, Krebs J . Five repair pathways in one context: chromatin modification during DNA repair. Biochem Cell Biol. 2006; 84(4):490-504. DOI: 10.1139/o06-075. View

15.

Tichy E, Stambrook P . DNA repair in murine embryonic stem cells and differentiated cells. Exp Cell Res. 2008; 314(9):1929-36. PMC: 2532524. DOI: 10.1016/j.yexcr.2008.02.007. View

16.

McNeill D, Wilson 3rd D . A dominant-negative form of the major human abasic endonuclease enhances cellular sensitivity to laboratory and clinical DNA-damaging agents. Mol Cancer Res. 2007; 5(1):61-70. DOI: 10.1158/1541-7786.MCR-06-0329. View

17.

Ehrlich M . DNA methylation in cancer: too much, but also too little. Oncogene. 2002; 21(35):5400-13. DOI: 10.1038/sj.onc.1205651. View

18.

Donawho C, Luo Y, Luo Y, Penning T, Bauch J, Bouska J . ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res. 2007; 13(9):2728-37. DOI: 10.1158/1078-0432.CCR-06-3039. View

19.

Li E, Bestor T, Jaenisch R . Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell. 1992; 69(6):915-26. DOI: 10.1016/0092-8674(92)90611-f. View

20.

Carlone D, Hart S, Ladd P, Skalnik D . Cloning and characterization of the gene encoding the mouse homologue of CpG binding protein. Gene. 2002; 295(1):71-7. DOI: 10.1016/s0378-1119(02)00820-x. View