Speakers
Howard Hughes Medical Institute Investigator
Details
Genomic instability is a hallmark of cancer, and policing this is therefore essential to life. For this and many other reasons, extensive DNA repair mechanisms are encoded in our genome. All of these require sensing of DNA damage as a prerequisite for action.
Acute exposure to ionizing radiation induces massive cell death and severe damage to tissues containing actively proliferating cells, including bone marrow and the gastrointestinal tract. However, the cellular and molecular mechanisms underlying this pathology remain controversial. We found that mice deficient in the double-strand DNA (dsDNA) sensor AIM2 are protected from irradiation-induced death. AIM2 mediates caspase-1-dependent death in response to dsDNA breaks caused by ionizing radiation and chemotherapeutic agents. Mechanistically, we found that AIM2 senses radiation-induced DNA damage in the nucleus to mediate inflammasome activation and cell death. Thus AIM2 is a sensor of genomic integrity.