Updated project metadata. Cytosine deamination to uracil in DNA leads to mutations if the DNA lesion is not corrected. Base excision repair (BER) initiated by single-strand selective uracil-DNA glycosylase 1 (SMUG1) primarily recognizes uracil and oxidized pyrimidines, and processes them to restore the correct bases. SMUG1 status has been associated with cancer risk and therapeutic response as high levels of SMUG1 were observed in breast carcinomas and other cancer types. The role of SMUG1 in breast cancer is not completely understood. Here, we define a bad prognosis signature for SMUG1 interactors in different cancers by mapping out a SMUG1 interaction network. Survival analyses of patient outcomes show that high expression of genes in the bad prognosis network correlates with lower survival probability in breast cancer. Interestingly, bioinformatics analyses suggested let-7b-5p microRNA as one of the upstream regulators of SMUG1 interactors. Expression of SMUG1 and let-7b-5p are negatively correlated in breast cancer and we observed an inhibitory auto-regulatory loop between SMUG1 and let-7b-5p in MCF-7 cells. Hence, SMUG1 is a key player connecting RNA and DNA metabolism with regulation of gene expression.