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

Courtney M. Tate, Melissa Fishel, Julianne L. Holleran, Merrill J. Egorin, David G. Skalnik

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1411-1423
Number of pages13
JournalDNA Repair
Volume8
Issue number12
DOIs
StatePublished - Dec 3 2009

Fingerprint

Endonucleases
Embryonic Stem Cells
Stem cells
Epigenomics
Fingers
DNA
Proteins
DNA Repair
Repair
Methylation
Histones
Chromatin
DNA-(Apurinic or Apyrimidinic Site) Lyase
Amino Acids
Cytosine
Essential Genes
Methyltransferases
DNA Damage
Hypersensitivity
Genes

Keywords

  • Ape1/Ref-1
  • Cfp1
  • Chromatin
  • DNA damaging agents
  • Epigenetic regulation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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. / Tate, Courtney M.; Fishel, Melissa; Holleran, Julianne L.; Egorin, Merrill J.; Skalnik, David G.

In: DNA Repair, Vol. 8, No. 12, 03.12.2009, p. 1411-1423.

Research output: Contribution to journalArticle

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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.",
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