Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest

Kamyar Zahedi, John Bissler, Zhaohui Wang, Anuradha Josyula, Lu Lu, Paula Diegelman, Nick Kisiel, Carl W. Porter, Manoocher Soleimani

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Expression of spermidine/spermine N1-acetyltransferase (SSAT) increases in kidneys subjected to ischemia-reperfusion injury (IRI). Increased expression of SSAT in vitro leads to alterations in cellular polyamine content, depletion of cofactors and precursors of polyamine synthesis, and reduced cell proliferation. In our model system, a >28-fold increase in SSAT levels in HEK-293 cells leads to depletion of polyamines and elevation in the enzymatic activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase, suggestive of a compensatory reaction to increased polyamine catabolism. Increased expression of SSAT also led to DNA damage and G2 arrest. The increased DNA damage was primarily due to the depletion of polyamines. Other factors such as increased production of H2O2 due to polyamine oxidase activity may play a secondary role in the induction of DNA lesions. In response to DNA damage the ATM/ATR → Chk1/2 DNA repair and cell cycle checkpoint pathways were activated, mediating the G2 arrest in SSAT-expressing cells. In addition, the activation of ERK1 and ERK2, which play integral roles in the G2/M transition, is impaired in cells expressing SSAT. These results indicate that the disruption of polyamine homeostasis due to enhanced SSAT activity leads to DNA damage and reduced cell proliferation via activation of DNA repair and cell cycle checkpoint and disruption of Raf → MEK → ERK pathways. We propose that in kidneys subjected to IRI, one mechanism through which increased expression of SSAT may cause cellular injury and organ damage is through induction of DNA damage and the disruption of cell cycle.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume292
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

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Spermine
Polyamines
DNA Damage
Homeostasis
Epithelial Cells
Kidney
Cell Cycle Checkpoints
Reperfusion Injury
DNA Repair
Adenosylmethionine Decarboxylase
Cell Proliferation
Ornithine Decarboxylase
diamine N-acetyltransferase
MAP Kinase Signaling System
HEK293 Cells
Cell Cycle
DNA
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology

Cite this

Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest. / Zahedi, Kamyar; Bissler, John; Wang, Zhaohui; Josyula, Anuradha; Lu, Lu; Diegelman, Paula; Kisiel, Nick; Porter, Carl W.; Soleimani, Manoocher.

In: American Journal of Physiology - Cell Physiology, Vol. 292, No. 3, 01.03.2007.

Research output: Contribution to journalArticle

Zahedi, Kamyar ; Bissler, John ; Wang, Zhaohui ; Josyula, Anuradha ; Lu, Lu ; Diegelman, Paula ; Kisiel, Nick ; Porter, Carl W. ; Soleimani, Manoocher. / Spermidine/spermine N1-acetyltransferase overexpression in kidney epithelial cells disrupts polyamine homeostasis, leads to DNA damage, and causes G2 arrest. In: American Journal of Physiology - Cell Physiology. 2007 ; Vol. 292, No. 3.
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