Histone variant H3.3 mediates cGAS-STING pathway activation via telomere deprotection

Telomeric deposition of histone variant H3.3 is controlled by ATRX, DAXX, HIRA, and ASF1 proteins. Point mutations of H3.3 and defective mutants of ATRX are associated with cancers that utilize the alternative lengthening of telomeres (ALT) pathway to protect and maintain chromosome ends. Here, we identify a cascade of events following the expression of a TRF2 dominant negative mutant, TRF2ΔBΔM, which are regulated by H3.3 expression. H3.3 regulates the formation of damaged foci at telomeres and subsequent telomere-to-telomere fusion events controlled by the DNA repair pathway. Telomere fusion events also contributes to the formation of micronuclei and abnormal segregation. Micronuclei formation triggers activation of the cGAS-STING mediated innate immune response to intracellular DNA and inhibits cell growth. All of these phenotypes are controlled by the expression of H3.3. Additionally, disruption of ATRX, DAXX, HIRA, or ASF1 elicits an impairment phenotype similar to that is caused by H3.3 inhibition. Our results indicate that cGAS-STING-mediated cellular senescence is triggered by deprotected telomeres and is controlled by the expression and deposition of H3.3 on telomeres.