DNA damage triggers tubular endoplasmic reticulum extension to promote apoptosis by facilitating ER-mitochondria signaling

Cell Res. 2018 Aug;28(8):833-854. doi: 10.1038/s41422-018-0065-z. Epub 2018 Jul 20.


The endoplasmic reticulum (ER) is composed of the nuclear envelope, perinuclear sheets and a peripheral tubular network. The peripheral ER and mitochondria form tight contacts at specific subdomains, which coordinate the functions of the two organelles and are required for multiple cellular processes such as Ca2+ transfer and apoptosis. However, it is largely unknown how ER morphology and ER-mitochondria signaling are dynamically regulated under different physiological or pathological conditions such as DNA damage. Here we show that the peripheral, tubular ER undergoes significant extension in response to DNA damage, and that this process is dependent on p53-mediated transcriptional activation of the ER-shaping proteins REEP1, REEP2 and EI24 (alias PIG8). This promotes the formation of ER-mitochondria contacts through EI24 and the mitochondrial outer membrane protein VDAC2, facilitates Ca2+ transfer from ER to mitochondria and promotes DNA damage-induced apoptosis. Thus, we identify a unique DNA damage response pathway involving alterations in ER morphology, ER-mitochondria signaling, and apoptosis.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis*
  • Calcium / metabolism*
  • Cell Line
  • DNA Damage*
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Male
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Nuclear Proteins / metabolism
  • Signal Transduction
  • Tumor Suppressor Protein p53 / metabolism*
  • Voltage-Dependent Anion Channel 2 / metabolism


  • Apoptosis Regulatory Proteins
  • EI24 protein, human
  • EI24 protein, mouse
  • Membrane Proteins
  • Membrane Transport Proteins
  • Nuclear Proteins
  • REEP1 protein, human
  • REEP2 protein, mouse
  • Tumor Suppressor Protein p53
  • VDAC2 protein, human
  • Voltage-Dependent Anion Channel 2
  • Calcium