Related Experiment Video
Updated: Jul 6, 2025
06:21
Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
Published on: May 10, 2024
725
MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis
Min-Guk Cho1, Rashmi J Kumar1,2, Chien-Chu Lin3
1Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nature
|January 10, 2024
Summary
The MRE11 complex releases cGAS from inhibition, enabling DNA damage-induced activation. This process suppresses breast cancer by triggering necroptosis, highlighting MRE11
Area of Science:
- Molecular Biology
- Immunology
- Cancer Research
Background:
- Oncogene-induced replication stress causes DNA damage, activating cGAS-STING signaling for tumor suppression.
- The mechanism of cGAS activation by endogenous DNA damage is unclear, as histone binding inhibits it.
- MRE11 (meiotic recombination 11) is a DNA double-strand break sensor involved in DNA repair.
Purpose of the Study:
- To elucidate the role of MRE11 in regulating cGAS activation by endogenous DNA damage.
- To investigate the mechanism by which MRE11 facilitates cGAS activation.
- To determine the downstream consequences of MRE11-mediated cGAS activation in tumor suppression.
Main Methods:
- Investigated the interaction between MRE11-RAD50-NBN complex, nucleosomes, and cGAS.
- Assessed the necessity of MRE11 for cGAS activation in response to oncogenic stress, dsDNA, and ionizing radiation.
- Analyzed the role of MRE11-dependent cGAS activation in ZBP1-RIPK3-MLKL-mediated necroptosis and tumor suppression.
Main Results:
- MRE11 binding to nucleosome fragments displaces cGAS from inhibitory histone interactions, enabling dsDNA-dependent activation.
- MRE11 is essential for cGAS activation by endogenous DNA damage, cytosolic dsDNA, and ionizing radiation.
- MRE11-mediated cGAS activation promotes ZBP1-RIPK3-MLKL-dependent necroptosis, suppressing mammary tumorigenesis.
Conclusions:
- MRE11 acts as a crucial mediator linking DNA damage to cGAS activation.
- MRE11-dependent cGAS activation suppresses breast cancer through ZBP1-mediated necroptosis.
- Downregulation of ZBP1 correlates with poor prognosis in triple-negative breast cancer.
More Related Videos
Related Concept Videos
02:23Abnormal Proliferation
4.5K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
03:03mTOR Signaling and Cancer Progression
3.8K
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
3.8K
01:46Epigenetic Regulation
31.1K
Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
31.1K
02:54Nucleosome Remodeling
9.1K
Nucleosomes are the basic units of chromatin compaction. Each nucleosome consists of the DNA bound tightly around a histone core, which makes the DNA inaccessible to DNA binding proteins such as DNA polymerase and RNA polymerase. Hence, the fundamental problem is to ensure access to DNA when appropriate, despite the compact and protective chromatin structure.
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
Nucleosome remodeling complex
Eukaryotic cells have specialized enzymes called ATP-dependent nucleosome remodeling enzymes. These enzymes...
9.1K
02:23Master Transcription Regulators
6.9K
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
6.9K
02:38Mitogens and the Cell Cycle
6.5K
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...
6.5K