Base-excision repair (BER) is a central DNA repair mechanism responsible for the maintenance of genome integrity. However, prolonged exposure of cells to pro-inflammatory molecules or DNA-damaging agents causes a BER deficiency by downregulating the central scaffold protein XRCC1. The rationale for this XRCC1 downregulation in response to persistent DNA damage remains enigmatic. Here, we demonstrate that persistent single-strand breaks (SSBs) caused by XRCC1 downregulation trigger the integrated stress response (ISR) to promote cellular survival under nutrient-restricted conditions. Thus, our results uncover a previously unappreciated connection between persistent DNA damage, caused by a decrease in BER capacity or direct induction of DNA damage, and the ISR pathway that supports cell survival in response to genotoxic stress with implications for tumour biology and beyond.
Cancer-associated stroma (CAS) plays a key role in cancer initiation and progression, but stromal changes in benign forms of naturally occurring tumours remain poorly characterized. Spontaneous canine mammary carcinomas (mCA) are viewed as excellent models of human mCA. By analyzing stroma isolated from formalin-fixed paraffin embedded patient samples, we find that the stroma of beningn tumours undergoes strong reprogramming, we identify clear stromal changes between benign and malignant mammary tumours, and identify strongly discriminatory genes between adenomas and carcinomas with prognostic value for human breast cancer. Given the relevance of canine CAS as a model for the human disease, our approach identifies disease- modulating stromal components with implications for both human and canine breast cancer.
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