Transcription pattern of p53-targeted DNA repair genes in the hypoxia-tolerant subterranean mole rat Spalax

Imad Shams, Assaf Malik, Irena Manov, Alma Joel, Mark Band, Aaron Avivi

Research output: Contribution to journalArticlepeer-review

Abstract

The tumor suppressor gene p53 induces growth arrest and/or apoptosis in response to DNA damage/hypoxia. Inactivation of p53 confers a selective advantage to tumor cells under a hypoxic microenvironment during tumor progression. The subterranean blind mole rat, Spalax, spends its life underground at low-oxygen tensions, hence developing a wide range of respiratory/molecular adaptations to hypoxic stress, including critical changes in p53 structure and signaling pathway. The highly conserved p53 Arg(R)-172 is substituted by lysine (K) in Spalax, identical with a tumor-associated mutation. Functionality assays revealed that Spalax p53 is unable to activate apoptotic target genes but is still capable of activating cell cycle arrest genes. Furthermore, we have shown that the transcription patterns of representative p53-induced genes (Apaf1 and Mdm2) in Spalax are influenced by hypoxia. Cell cycle arrest allows the cells to repair DNA damage via different DNA repair genes. We tested the transcription pattern of three p53-related DNA repair genes (p53R2, Mlh1, and Msh2) under normoxia and short-acute hypoxia in Spalax, C57BL/6 wild-type mice, and two strains of mutant C57BL/6 mice, each carrying a different mutation at the R172 position. Our results show that while wild-type/mutant mice exhibit strong hypoxia-induced reductions of repair gene transcript levels, no such inhibition is found in Spalax under hypoxia. Moreover, unlike mouse p53R2, Spalax p53R2 transcript levels are strongly elevated under hypoxia. These results suggest that critical repair functions, which are known to be inhibited under hypoxia in mice, remain active in Spalax, as part of its unique hypoxia tolerance mechanisms.

Original languageEnglish
Pages (from-to)1111-1118
Number of pages8
JournalJournal of Molecular Biology
Volume425
Issue number7
DOIs
StatePublished - 12 Apr 2013

Bibliographical note

Funding Information:
This study was supported by the U.S.–Israel Binational Science Foundation Grant to A.A. and M.B. We thank Prof. Moshe Oren from the Weizmann Institute of Science (Rehovot, Israel) for the p53-R172H mice and Prof. Guillermina Lozano from the M.D. Anderson Cancer Center, the University of Texas (Houston, TX, USA) for the p53-R172P mice.

Keywords

  • cancer
  • hypoxia
  • p53-targeted DNA repair genes
  • subterranean mole rat

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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