Cargando…

cGAS surveillance of micronuclei links genome instability to innate immunity

DNA is strictly compartmentalised within the nucleus to prevent autoimmunity1; despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage2–6. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS...

Descripción completa

Detalles Bibliográficos
Autores principales: Mackenzie, Karen J., Carroll, Paula, Martin, Carol-Anne, Murina, Olga, Fluteau, Adeline, Simpson, Daniel, Olova, Nelly, Sutcliffe, Hannah, Rainger, Jacqueline, Robertson, Andrea, Osborn, Ruby, Wheeler, Ann, Nowotny, Marcin, Gilbert, Nick, Chandra, Tamir, Reijns, Martin A. M., Jackson, Andrew P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870830/
https://www.ncbi.nlm.nih.gov/pubmed/28738408
http://dx.doi.org/10.1038/nature23449
Descripción
Sumario:DNA is strictly compartmentalised within the nucleus to prevent autoimmunity1; despite this cGAS, a cytosolic sensor of dsDNA, is activated in autoinflammatory disorders and by DNA damage2–6. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localises to micronuclei arising from genome instability in a model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. These micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by their own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis7, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS binds to and is activated by chromatin and, consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA-damage are cell-cycle dependent. Furthermore, by combining live-cell laser microdissection with single cell transcriptomics, we establish that induction of interferon stimulated gene expression occurs in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, cGAS recognition of micronuclei may act as a cell-intrinsic immune surveillance mechanism detecting a range of neoplasia-inducing processes.