XRCC1 deficiency drives telomeric chromatin leakage, inflammatory signalling and senescence.

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 to better dissect the mechanisms through which these factors safeguard genome integrity. We show that XRCC1 deficiency, more than APE1 depletion, leads to an increase of the DNA damage signalling, and the formation of cytoplasmic chromatin fragments (CCFs) containing telomeric DNA. XRCC1-deficient cells also exhibit activation of the cGAS-STING pathway, inflammatory signalling, and senescence phenotypes. Our findings identify XRCC1 as a central suppressor of oxidative stress-induced cytosolic DNA accumulation and immune signalling. These results suggest that targeting XRCC1 may offer a therapeutic avenue to trigger tumour senescence and promote anti-tumour immunity.