XRCC1 Deficiency Drives Telomeric Chromatin Leakage, Inflammatory signaling and Senescence in Cancer Cells

Genome integrity is constantly challenged by oxidative DNA damage, which, if left unrepaired, can result in replication stress, chromosomal instability, and tumorigenesis. The base excision repair (BER) pathway is essential for resolving oxidative base lesions such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG). Among BER factors, APE1 and XRCC1 play critical roles not only in lesion repair but also in maintaining replication fork stability. Here, we investigate the cellular consequences of APE1 and XRCC1 deficiency in isogenic breast epithelial models (MCF10A and MCF7), under basal and oxidative stress conditions. We show that XRCC1 deficiency, more than APE1 depletion, leads to accumulation of unrepaired BER intermediates, increased DNA damage signaling, and formation of cytoplasmic chromatin fragments (CCFs) containing 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 chromatin instability, cytosolic DNA accumulation, and immune signaling. These results suggest that targeting BER in carcer, particularly XRCC1, may offer a therapeutic avenue to trigger tumor-selective senescence and promote anti-tumor immunity.