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

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.