Piscone, Anna (2025) BER deficiency studies reveal a role for XRCC1 in telomere stability, inflammation, and cancer cell senescence. [Tesi di dottorato]

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Abstract

The base excision repair (BER) pathway is the primary mechanism that safeguards genome integrity against oxidative DNA damage. Particularly, BER pathway plays a central role in removing oxidative base lesions, such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). When this pathway is impaired or overwhelmed by excessive oxidative stress, unrepaired oxidative DNA lesions and toxic repair intermediates can accumulate, thereby interfering with replication fork progression and ultimately driving replication stress and genome instability. Consistently, impaired BER has been associated with cancer, aging, and several age-related disorders. Since genomic instability is a hallmark of these conditions, a deeper investigation into the role of BER in safeguarding genome integrity is pivotal to clarifying the molecular bases of these conditions and identifying novel therapeutic opportunities. Here, we investigated the functional consequences of impairing two central BER components, Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) and X-ray Repair Cross-Complementing Protein 1 (XRCC1), in isogenic breast epithelial models (MCF10A and MCF7). By comparing cells under physiological and oxidative stress conditions, we aimed to define the specific contributions of these proteins in genome stability. We found that XRCC1 deficiency, rather than APE1 depletion, leads to accumulation of DSBs, increased DNA damage signaling, and formation of cytoplasmic chromatin fragments (CCFs) enriched in telomeric DNA. XRCC1-deficient cells also exhibit activation of the cGAS-STING pathway, inflammatory signaling, and features of senescence. Our findings identify XRCC1 as a central suppressor of oxidative stress-induced genome instability, cytosolic DNA accumulation, and immune signaling. Moreover, they suggest that targeting BER, particularly XRCC1, could represent a therapeutic strategy to induce tumor-selective senescence while simultaneously promoting anti-tumor immunity.

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