Article thumbnail

Targeting Protective Autophagy Exacerbates UV-Triggered Apoptotic Cell Death

By Li-Hsin Chen, Pei-Ming Chu, Yi-Jang Lee, Pang-Hsien Tu, Chin-Wen Chi, Hsin-Chen Lee and Shih-Hwa Chiou


Autophagy is activated by various stresses, including DNA damage, and previous studies of DNA damage-induced autophagy have focused on the response to chemotherapeutic drugs, ionizing radiation, and reactive oxygen species. In this study, we investigated the biological significance of autophagic response to ultraviolet (UV) irradiation in A549 and H1299 cells. Our results indicated that UV induces on-rate autophagic flux in these cells. Autophagy inhibition resulting from the knockdown of beclin-1 and Atg5 reduced cell viability and enhanced apoptosis. Moreover, we found that ATR phosphorylation was accompanied by microtubule-associated protein 1 light chain 3B II (LC3B-II) expression during the early phases following UV irradiation, which is a well-established inducer of ATR. Knocking down ATR further attenuated the reduction in LC3B-II at early stages in response to UV treatment. Despite the potential role of ATR in autophagic response, reduced ATR expression does not affect autophagy induction during late phases (24 and 48 h after UV treatment). The result is consistent with the reduced ATR phosphorylation at the same time points and suggests that autophagic response at this stage is activated via a distinct pathway. In conclusion, this study demonstrated that autophagy acts as a cytoprotective mechanism against UV-induced apoptosis and that autophagy induction accompanied with apoptosis at late stages is independent of ATR activation

Topics: Article
Publisher: Molecular Diversity Preservation International (MDPI)
OAI identifier:
Provided by: PubMed Central

Suggested articles


  1. (2005). Ataxia telangiectasia mutated (ATM) and ATM and Rad3-related protein exhibit selective target specificities in response to different forms of DNA damage.
  2. (2001). ATM and ATR: Networking cellular responses to DNA damage.
  3. (2006). ATM- and cell cycle-dependent regulation of ATR
  4. (2001). ATR and ATRIP: Partners in checkpoint signaling. Science
  5. (2011). ATR controls the p21 WAF1/Cip1 protein up-regulation and apoptosis in response to low UV fluences.
  6. (2000). ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev.
  7. (2009). ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: Potential basis for the UV protective effects of caffeine.
  8. (2006). ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling.
  9. (2008). ATR: An essential regulator of genome integrity.
  10. (2005). Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ.
  11. (2007). Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ.
  12. Autophagy inhibition enhances apoptosis triggered by BO-1051, an N-mustard derivative, and involves the ATM signaling pathway.
  13. (2008). Autophagy is cytoprotective during cisplatin injury of renal proximal tubular cells. Kidney Int.
  14. (2012). Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor.
  15. (2008). Cisplatin treatment of NIH/3T3 cultures induces a form of autophagic death in polyploid cells.
  16. (2008). Compensatory mechanisms and the type of injury determine the fate of cells with impaired macroautophagy. Autophagy
  17. (2008). death and burial: Multifaceted impact of autophagy.
  18. (2006). Differential mechanisms of conjunctival cell death induction by ultraviolet irradiation and benzalkonium chloride.
  19. (2001). Dissection of autophagosome formation using Apg5-deficient mouse embryonic stem cells.
  20. (2006). DNA damage-induced cell death by apoptosis. Trends Mol. Med.
  21. (2009). G-quadruplex ligand SYUIQ-5 induces autophagy by telomere damage and TRF2 delocalization in cancer cells. Mol. Cancer Ther.
  22. (2008). Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy
  23. (1999). Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature
  24. (2008). Loss of macroautophagy promotes or prevents fibroblast apoptosis depending on the death stimulus.
  25. (2009). Mouse models for ATR deficiency. DNA Repair (Amst)
  26. (2002). Preferential binding of ATR protein to UV-damaged DNA.
  27. (1999). Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation.
  28. (2006). Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex. Oncogene
  29. Self-eating and self-killing: Crosstalk between autophagy and apoptosis.
  30. (2000). Sensing and responding to DNA damage.
  31. Sensitization to radiation-induced DNA damage accelerates loss of bcl-2 and increases apoptosis and autophagy.
  32. (2008). To die or not to die: That is the autophagic question.

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.