Autophagy promotes DNA-protein crosslink clearance

Mutat Res Genet Toxicol Environ Mutagen. 2016 Feb:797:21-5. doi: 10.1016/j.mrgentox.2015.12.001. Epub 2015 Dec 14.


Toxic DNA-protein crosslinks (DPCs) can result from exposure to radiation or chemotherapeutic agents. DPCs can also accumulate during aging or stress. However, the cellular mechanisms underlying clearance of DPCs remain largely unknown. Here, we have identified an important role of autophagy in the processing of DPCs induced by three representative agents: formaldehyde, a chemical used widely in industry; UV light; and camptothecin, a cytotoxic anticancer drug. Autophagy inhibitors, 3-methyladenine (3-MA) or chloroquine (CQ), promoted the accumulation of DPCs in damaged cells and injured organs. siRNA-mediated silencing of Atg5 or Atg7, two essential components for the formation of the autophagosome, gave similar results. In contrast, the autophagy inducer rapamycin (RAP) attenuated DPCs in vitro and in vivo. Our findings reveal the importance of autophagy in controlling the level of DPCs, and may open up a new avenue for understanding the formation and clearance of this detrimental DNA adduct.

Keywords: Autophagy; DNA–protein crosslinks; Formaldehyde.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Autophagy / drug effects*
  • Autophagy-Related Protein 5
  • Autophagy-Related Protein 7
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chloroquine / pharmacology
  • DNA Damage / drug effects*
  • Formaldehyde / pharmacology
  • Gene Silencing
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Sirolimus / pharmacology
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism
  • Ultraviolet Rays


  • ATG5 protein, human
  • Antineoplastic Agents
  • Autophagy-Related Protein 5
  • Microtubule-Associated Proteins
  • RNA, Small Interfering
  • Formaldehyde
  • 3-methyladenine
  • Chloroquine
  • ATG7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes
  • Adenine
  • Sirolimus
  • Camptothecin