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March 31st, 2025
Version: 2
Molecular and Cell Biology, Taiwan International Graduate Program, Academia Sinica and Graduate Institute of Life Science, National Defense Medical Center, Taip
molecular biology
biorxiv

Histone Variant H3.3 Mediates DNA Repair and cGAS-STING Pathway Activation in Telomere Dysfunction

Huang, C.-M.•Chen, L.-Y.

The telomere damage response is a critical mechanism that regulates cellular senescence. Deprotected telomeres activate the cytosolic DNA sensing cGAS-STING pathway, leading to cellular senescence. Our previous studies revealed that extrachromosomal telomere repeats (ECTRs) activate the cGAS-STING pathway, and this process is attenuated by histone H3.3 depletion. However, the role of histone H3.3 in telomere deprotection-dependent cGAS-STING pathway activation 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 findings 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, emphasizing the importance of this pathway in cellular senescence.

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