(2020). Regulation and Consequences of cGAS Activation by Self-DNA. Trends in cell biology,
(2020). Structural basis for the inhibition of cGAS by nucleosomes. Science,
The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) senses invasion of pathogenic DNA and stimulates inflammatory signaling, autophagy, and apoptosis. Organization of host DNA into nucleosomes was proposed to limit cGAS autoinduction, but the underlying mechanism was unknown. Here, we report the structural basis for this inhibition. In the cryo-electron microscopy structure of the human cGAS-nucleosome core particle (NCP) complex, two cGAS monomers bridge two NCPs by binding the acidic patch of the histone H2A-H2B dimer and nucleosomal DNA. In this configuration, all three known cGAS DNA binding sites, required for cGAS activation, are repurposed or become inaccessible, and cGAS dimerization, another prerequisite for activation, is inhibited. Mutating key residues linking cGAS and the acidic patch alleviates nucleosomal inhibition. This study establishes a structural framework for why cGAS is silenced on chromatinized self-DNA..
(2019). The Cytoplasmic DNA Sensor cGAS Promotes Mitotic Cell Death. Cell,
(2018). Nucleosome-Dependent Pathways That Control Mitotic Progression. Cold spring harb symp quant biol,
The majority of eukaryotic chromosomal DNA exists in the form of nucleosomes, where ∼147 bp DNA wraps around histone hetero-octamers, composed of histone H3, H4, H2A, and H2B. Despite their obvious importance in DNA compaction and accessibility, studying their specific roles, such as regulation of mitotic progression, in a physiological environment is associated with critical caveats because of their major contributions in transcriptional control. Through establishing a method to deplete endogenous histones H3 and H4 from frog egg extracts and complementing their functions using recombinant nucleosome arrays, we are now able to analyze their roles in mitotic progression without affecting overall transcriptomic profiles. Here we summarize advancements learned from this system, illustrating that microtubule and nuclear envelope assembly can be regulated by two major nucleosome-bound protein complexes, RCC1-Ran and the chromosomal passenger complex (CPC) containing the mitotic protein kinase Aurora B. We also discuss roles of the CPC on the proteomic composition of mitotic chromatin. The CPC promotes dissociation of a variety of nucleosome remodelers and DNA repair pathway proteins, suggesting its role in suppressing DNA processing activities on mitotic chromosomes. We speculate that this suppression particularly on chromosomes under microtubule tension may be important to preserve genome integrity..
van den Boom, J.
(2016). VCP/p97 Extracts Sterically Trapped Ku70/80 Rings from DNA in Double-Strand Break Repair. Molecular cell,
(2015). Nucleosome functions in spindle assembly and nuclear envelope formation. Bioessays,
(2014). Nucleosomal regulation of chromatin composition and nuclear assembly revealed by histone depletion. Nature structural & molecular biology,
(2010). Survivin Reads Phosphorylated Histone H3 Threonine 3 to Activate the Mitotic Kinase Aurora B. Science,
Location, Location, Location
Cell division is orchestrated by a complex signaling pathway that ensures the correct segregation of newly replicated chromosomes to the two daughter cells. The pathway is controlled in part by restricting the activity of critical regulators to specific subcellular locations. For example, the chromosomal passenger complex (CPC) is recruited to chromosomes during mitosis where it oversees kinetochore activity and cytokinesis (see Perspective by
, published online 12 August),
, published online 12 August), and
) now show that the phosphorylation of the chromatin protein, histone H3, acts to bring the CPC to chromosomes, thereby activating its aurora B kinase subunit. The Survivin subunit of CPC binds specifically to phosphorylated H3, with the phosphorylation at centromeres being carried out by the mitosis-specific kinase, haspin. Furthermore, Bub1 phosphorylation of histone H2A recruits shugoshin, a centromeric CPC adapter. Thus, these two histone marks in combination define the inner centromere.
(2008). Break dosage, cell cycle stage and DNA replication influence DNA double strand break response. The embo journal,
(2004). Mnd1 Is Required for Meiotic Interhomolog Repair. Current biology,