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Antecedent chromatin organization determines cGAS recruitment to ruptured micronuclei

Kate M MacDonald1, Shirony Nicholson-Puthenveedu2, Maha M Tageldein1

  • 1Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.

Nature Communications
|February 2, 2023
PubMed

Insights

Micronuclei (MN) rupture allows cyclic GMP-AMP synthase (cGAS) to initiate interferon signaling. Specific chromatin features within MN regulate cGAS recruitment and the cellular DNA damage response.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Micronuclei (MN) are critical in DNA damage response.
  • Their rupture can trigger innate immune signaling via cyclic GMP-AMP synthase (cGAS).
  • The precise mechanisms regulating cGAS activation by MN remain incompletely understood.

Purpose of the Study:

  • To investigate the role of chromatin characteristics and intra-MN dynamics in cGAS recruitment.
  • To elucidate how these factors influence the interferon signaling cascade downstream of DNA damage.

Main Methods:

  • Analysis of histone modifications (H3K79me2) in MN.
  • Assessment of transcriptional activity within MN.
  • Investigation of MN chromatin tethering mechanisms.
  • Evaluation of cGAS localization and interferon signaling activation.

Main Results:

  • MN rupture is necessary but not sufficient for cGAS localization.
  • Specific chromatin features, like H3K79me2, are retained in MN and regulate cGAS recruitment.
  • Intra-MN transcriptional dynamics influence cGAS responsiveness.
  • Nucleosome acidic patch tethering of MN chromatin is essential for cGAS-dependent signaling.

Conclusions:

  • Cellular chromatin status before DNA damage and organizational changes within MN dictate cGAS recruitment.
  • Micronuclei act as integrative signaling hubs coordinating the cellular response to genotoxic stress.
  • These findings offer new insights into DNA damage sensing and innate immunity.

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