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

The telomere damage response is a critical mechanism regulating human aging and disease progression. Deprotected telomeres activate the cytosolic DNA-sensing cGAS-STING pathway; however, the underlying mechanism remains unclear. Here, we discover that histone H3.3 is required for cGAS-STING pathway activation in cells with deprotected telomeres. Expression of the TRF2 dominant-negative mutant, TRF2{Delta}B{Delta}M, induces telomere dysfunction in fibroblast cells, triggering cGAS-STING pathway activation and growth inhibition. Histone H3.3 depletion significantly reduces this activation, highlighting its critical role in linking telomere deprotection to the cGAS-STING-mediated innate immune signaling. Furthermore, we assess the role of histone H3.3 in telomere fusion. Our finding reveal that histone H3.3 regulates cGAS-STING signaling by controlling telomere fusion. Additionally, depletion of histone H3.3 chaperones, including ATRX, DAXX, and HIRA, inhibits telomere fusion and cGAS-STING pathway activation, underscoring the role of histone H3.3 in telomere maintenance and the DNA damage response. Collectively, our study establishes histone H3.3 as a key regulator of telomere fusion and telomere dysfunction-induced cGAS-STING pathway activation, revealing the correlation between histones and telomeric DNA damage response.