Related Experiment Video

Updated: Oct 12, 2025

Capturing Common Fragile Site Breaks by Native γH2A.X ChIP
09:46

Capturing Common Fragile Site Breaks by Native γH2A.X ChIP

Published on: January 24, 2025

453

Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells

Patrick J Flynn1, Peter D Koch2, Timothy J Mitchison1

  • 1Department of Systems Biology, Harvard Medical School, Boston, MA 02115; patrick_flynn@hms.harvard.edu timothy_mitchison@hms.harvard.edu.

Proceedings of the National Academy of Sciences of the United States of America
|November 25, 2021
PubMed

Insights

Mitotic errors activate cyclic GMP-AMP synthase (cGAS) by stretching chromatin bridges, not micronuclei, inducing type I interferon (IFN) signaling. This finding reveals a new mechanism for immune surveillance and potential anti-cancer drug targets.

Area of Science:

  • Cell Biology
  • Immunology
  • Molecular Biology

Background:

  • Mitotic errors can trigger innate immune responses via cyclic GMP-AMP synthase (cGAS) and type I interferon (IFN) signaling.
  • Existing models suggest micronuclei rupture activates cGAS following chromosome segregation errors.

Purpose of the Study:

  • To investigate the precise mechanism of cGAS activation during mitotic errors.
  • To determine the role of abnormal nuclear morphologies in cGAS activation and IFN signaling.

Main Methods:

  • Human fibroblasts were treated with antimitotic drugs to induce mitotic errors.
  • Abnormal nuclear morphologies, cGAS localization, and IFN signaling were measured.
  • cGAS activation was assessed in cancer cell lines and mouse cells.

Main Results:

  • Micronuclei recruited cGAS but did not activate it.
  • Interferon signaling correlated with cGAS-coated chromatin bridges, particularly those induced by microtubule stabilizers and MPS1 inhibitors.
  • cGAS activation by chromatin bridges was dependent on cytokinesis and occurred when chromatin was stretched.

Conclusions:

  • cGAS is activated by stretched chromatin bridges during failed mitosis, not by micronuclei.
  • This mechanism contributes to immune surveillance of mitotic errors and may underlie the antitumor effects of certain drugs.
  • Targeting cGAS activation by chromatin bridges could offer new therapeutic strategies.
Keywords:
cGAScancerchemotherapyinterferonmitosis

More Related Videos

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage10:44

Laser Microirradiation to Study In Vivo Cellular Responses to Simple and Complex DNA Damage

Published on: January 31, 2018

10.4K
Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers10:28

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Published on: September 20, 2018

6.6K

Related Concept Videos

DNA Damage can Stall the Cell Cycle02:37

DNA Damage can Stall the Cell Cycle

In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.5K
Inheritance of Chromatin Structures03:17

Inheritance of Chromatin Structures

Epigenetics is the study of inherited changes in a cell's phenotype without changing the DNA sequences. It provides a form of memory for the differential gene expression pattern to maintain cell lineage, position-effect variegation, dosage compensation, and maintenance of chromatin structures such as telomeres and centromeres. For example, the structure and location of the centromere on chromosomes are epigenetically inherited. Its functionality is not dictated or ensured by the underlying...
6.8K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
7.1K
M-Cdk Drives Transition Into Mitosis02:15

M-Cdk Drives Transition Into Mitosis

Checkpoints throughout the cell cycle serve as safeguards and gatekeepers, allowing the cell cycle to progress in favorable conditions and slow or halt it in problematic ones. This regulation is known as the cell cycle control system.
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
5.7K
Separation of Sister Chromatids02:17

Separation of Sister Chromatids

At the transition from prophase to metaphase, there is a reduction in cohesion along the chromosomal arms, resulting in the resolution of sister chromatids. However, residual cohesin connections remain to hold the sister chromatids together until the transition from metaphase to anaphase. The residual connection prevents any premature separation of sister chromatids, blocking the risks of aneuploidy within the daughter cells.
At the onset of anaphase, separase, a proteolytic enzyme, is...
3.9K
Crossing Over01:30

Crossing Over

Crossing over is the exchange of genetic information between homologous chromosomes during prophase I of meiosis I. Genetic recombination gives rise to allelic diversity in the newly formed daughter cells. In humans, crossing over produces genetically distinct haploid egg and sperm cells that undergo fertilization to produce unique offspring. Before cell division starts, the germ cell’s chromosome(s) undergo duplication in the S phase of the cell cycle. As the cells enter prophase I,...
4.9K