Altered gene expression profiles and higher frequency of spontaneous DNA strand breaks in APEX2-null thymus

Yukihiko Dan, Yutaka Ohta, Daisuke Tsuchimoto, Ohno Mizuki, Yasuhito Ide, Manabu Sami, Tomomasa Kanda, Sakumi Kunihiko, Yusaku Nakabeppu

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

A second class II AP endonuclease, APEX2, possesses strong 3′-5′ exonuclease and 3′-phosphodiesterase activities but only very weak AP-endonuclease activity. APEX2 associates with proliferating cell nuclear antigen (PCNA), and the progression of S phase of the cell cycle is accompanied by its expression. APEX2-null mice exhibit severe dyslymphopoiesis in thymus as well as moderate dyshematopoiesis and growth retardation. Comparative gene expression profiling of wild-type and APEX2-null mice using an oligonucleotide microarray revealed that APEX2-null thymus has significantly altered gene expression profiles, reflecting its altered populations of thymocytes. Beyond these altered populations, APEX2-null thymus exhibits significant alterations in expression of genes involved in DNA replication, recombination and repair, including Apex1, Exo1 and Fen1 as well as master genes for the DNA damage response, such as E2f1, Chek1, and proapoptotic genes. We therefore examined the extent of DNA strand breakage, and found that both of single-strand breaks detected as comets and double-strand breaks detected as γH2AX foci were significantly higher in frequency in most APEX2-null thymocytes compared to wild-type thymocytes. This higher frequency of DNA breaks was accompanied by increased expression of PCNA and increased phosphorylation of p53 at Ser23 and to a lesser extent, at Ser18. The present study clearly demonstrates that APEX2-null lymphocytes have a higher frequency of DNA breaks, indicating that APEX2 may play an important role(s) during their generation and/or repair.

Original languageEnglish
Pages (from-to)1437-1454
Number of pages18
JournalDNA Repair
Volume7
Issue number9
DOIs
Publication statusPublished - Sep 1 2008

Fingerprint

Thymus
DNA Breaks
Thymocytes
Transcriptome
Gene expression
DNA-(Apurinic or Apyrimidinic Site) Lyase
Thymus Gland
Exonucleases
Proliferating Cell Nuclear Antigen
DNA
Genes
Recombinational DNA Repair
Null Lymphocytes
Phosphoric Diester Hydrolases
Gene Expression Profiling
Oligonucleotide Array Sequence Analysis
DNA Replication
S Phase
Repair
DNA Repair

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Altered gene expression profiles and higher frequency of spontaneous DNA strand breaks in APEX2-null thymus. / Dan, Yukihiko; Ohta, Yutaka; Tsuchimoto, Daisuke; Mizuki, Ohno; Ide, Yasuhito; Sami, Manabu; Kanda, Tomomasa; Kunihiko, Sakumi; Nakabeppu, Yusaku.

In: DNA Repair, Vol. 7, No. 9, 01.09.2008, p. 1437-1454.

Research output: Contribution to journalArticle

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