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ER-directed TREX1 limits cGAS activation at micronuclei.

Lisa Mohr1, Eléonore Toufektchan1, Patrick von Morgen1

  • 1Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Molecular Cell
|January 21, 2021
PubMed
Summary

The endoplasmic reticulum (ER) enzyme TREX1 degrades DNA within micronuclei, preventing immune overactivation. TREX1 mutations disrupt this process, linking ER tethering to autoimmune disease prevention.

Keywords:
APE1BAFSTINGTREX1cGASchromosome instabilitychromothripsisendoplasmic reticulummicronucleinuclear envelope

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Area of Science:

  • Cell Biology
  • Immunology
  • Genetics

Background:

  • Micronuclei, formed from chromosome mis-segregation, can trigger immune responses when their DNA is exposed.
  • Loss of micronuclear envelope integrity is a key step leading to DNA fragmentation and immune activation.

Purpose of the Study:

  • To investigate the role of the endoplasmic reticulum (ER)-associated nuclease TREX1 in regulating immune responses at micronuclei.
  • To elucidate the mechanism by which TREX1 prevents cytosolic DNA sensing and autoimmune reactions.

Main Methods:

  • Micronuclei purification and biochemical assays.
  • Analysis of TREX1 localization and function in relation to the ER and micronuclei.
  • Investigation of TREX1 mutations and their impact on cellular processes and immune activation.

Main Results:

  • TREX1 degrades micronuclear DNA upon envelope rupture, inhibiting cGAS activation.
  • The ER actively accesses ruptured micronuclei, facilitating TREX1's DNA degradation activity.
  • TREX1 mutations impair ER tethering, leading to aberrant TREX1 localization, increased DNA damage, and enhanced cGAS activation.

Conclusions:

  • ER-directed DNA resection by TREX1 is crucial for regulating cytosolic DNA sensing in chromosomally unstable cells.
  • TREX1's tethering to the ER is essential for preventing autoimmunity by controlling micronuclear DNA exposure and immune activation.