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ATR controls the p21(WAF1/Cip1) protein up-regulation and apoptosis in response to low UV fluences

Huda H Al-Khalaf1, Siti-Faujiah Hendrayani, Abdelilah Aboussekhra

  • 1King Faisal Specialist Hospital and Research Center, Department of Biological and Medical Research, Riyadh, KSA.

Molecular Carcinogenesis
|October 7, 2011
PubMed

Insights

The ATR protein kinase up-regulates p21(WAF1/Cip1) and inhibits apoptosis in response to low UV doses. This ATR-dependent regulation is crucial for cellular protection against UV-induced DNA damage.

Area of Science:

  • Cellular and Molecular Biology
  • DNA Damage Response
  • Apoptosis Regulation

Background:

  • p21(WAF1/Cip1) is a key inhibitor of cell cycle progression and apoptosis.
  • ATR is a critical protein kinase involved in DNA damage response.
  • The precise role of ATR in p21(WAF1/Cip1) regulation under UV stress is not fully understood.

Purpose of the Study:

  • To investigate the role of ATR in modulating p21(WAF1/Cip1) expression following UVC radiation.
  • To elucidate the mechanisms by which ATR influences apoptosis in response to low UV fluences.

Main Methods:

  • Upregulation and downregulation studies of p21(WAF1/Cip1) in human fibroblast and epithelial cells.
  • Assessment of ATR dependency using ATR-deficient cells and caffeine treatment.
  • Analysis of apoptosis markers including caspase 3, PARP cleavage, BAX, and BAK.
  • Investigation of proteasomal degradation pathways involving SKP2 ubiquitination.

Main Results:

  • p21(WAF1/Cip1) is upregulated by low UV fluences in an ATR-dependent manner in normal cells.
  • ATR deficiency or caffeine treatment leads to UV-induced downregulation of p21(WAF1/Cip1) via proteasomal degradation.
  • ATR inhibits apoptosis by preventing caspase 3 and PARP cleavage and repressing BAX/BAK.
  • ATR stabilizes p21(WAF1/Cip1) even without genotoxic stress.

Conclusions:

  • ATR plays a dual role in promoting cell survival after low-dose UV exposure by upregulating p21(WAF1/Cip1) and inhibiting apoptosis.
  • ATR-mediated regulation of p21(WAF1/Cip1) is crucial for maintaining genomic stability and preventing cell death under specific UV conditions.

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