A Regulatory Network Comprising Let-7 MiRNA and SMUG1 is Associated with Good Prognosis in ER+ Breast Tumours

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2022 Sep 26

PMID 36156150

Authors

Lisa Lirussi

Dilara Ayyildiz

Yan Liu

Nicola P Montaldo

Sergio Carracedo

Miriam R Aure

Laure Jobert

Xavier Tekpli

Joel Touma

Torill Sauer

Emiliano Dalla

Vessela N Kristensen

Jurgen Geisler

Silvano Piazza

Gianluca Tell

Hilde Nilsen

Affiliations

Soon will be listed here.

Abstract

Single-strand selective uracil-DNA glycosylase 1 (SMUG1) initiates base excision repair (BER) of uracil and oxidized pyrimidines. SMUG1 status has been associated with cancer risk and therapeutic response in breast carcinomas and other cancer types. However, SMUG1 is a multifunctional protein involved, not only, in BER but also in RNA quality control, and its function in cancer cells is unclear. Here we identify several novel SMUG1 interaction partners that functions in many biological processes relevant for cancer development and treatment response. Based on this, we hypothesized that the dominating function of SMUG1 in cancer might be ascribed to functions other than BER. We define a bad prognosis signature for SMUG1 by mapping out the SMUG1 interaction network and found that high expression of genes in the bad prognosis network correlated with lower survival probability in ER+ breast cancer. Interestingly, we identified hsa-let-7b-5p microRNA as an upstream regulator of the SMUG1 interactome. Expression of SMUG1 and hsa-let-7b-5p were negatively correlated in breast cancer and we found an inhibitory auto-regulatory loop between SMUG1 and hsa-let-7b-5p in the MCF7 breast cancer cells. We conclude that SMUG1 functions in a gene regulatory network that influence the survival and treatment response in several cancers.

Citing Articles

Small-molecule activator of SMUG1 enhances repair of pyrimidine lesions in DNA.

Gao Y, McPherson L, Adimoolam S, Suresh S, Wilson D, Das I DNA Repair (Amst). 2025; 146:103809.

PMID: 39879855 PMC: 11846699. DOI: 10.1016/j.dnarep.2025.103809.

Cancer prognosis using base excision repair genes.

Kim J, Kang S, Jo N, Kim S, Jang S Mol Cells. 2025; 48(2):100186.

PMID: 39828060 PMC: 11835649. DOI: 10.1016/j.mocell.2025.100186.

Emerging roles of bases modifications and DNA repair proteins in onco-miRNA processing: novel insights in cancer biology.

Mangiapane G, DAgostino V, Tell G Cancer Gene Ther. 2024; 31(12):1765-1772.

PMID: 39322751 DOI: 10.1038/s41417-024-00836-x.

Experimental capture of miRNA targetomes: disease-specific 3'UTR library-based miRNA targetomics for Parkinson's disease.

Hart M, Kern F, Fecher-Trost C, Krammes L, Aparicio E, Engel A Exp Mol Med. 2024; 56(4):935-945.

PMID: 38556547 PMC: 11059366. DOI: 10.1038/s12276-024-01202-5.

Construction of ceRNA prognostic model based on the CCR7/CCL19 chemokine axis as a biomarker in breast cancer.

Ma R, Guan X, Teng N, Du Y, Ou S, Li X BMC Med Genomics. 2023; 16(1):254.

PMID: 37864213 PMC: 10590005. DOI: 10.1186/s12920-023-01683-9.

References

Darwanto A, Theruvathu J, Sowers J, Rogstad D, Pascal T, Goddard 3rd W . Mechanisms of base selection by human single-stranded selective monofunctional uracil-DNA glycosylase. J Biol Chem. 2009; 284(23):15835-46. PMC: 2708880. DOI: 10.1074/jbc.M807846200. View

Wang H, Ren Y, Qian C, Liu J, Li G, Li Z . Over-expression of CDX2 alleviates breast cancer by up-regulating microRNA let-7b and inhibiting COL11A1 expression. Cancer Cell Int. 2020; 20:13. PMC: 6954621. DOI: 10.1186/s12935-019-1066-9. View

Li M, Guan X, Sun Y, Mi J, Shu X, Liu F . miR-92a family and their target genes in tumorigenesis and metastasis. Exp Cell Res. 2014; 323(1):1-6. DOI: 10.1016/j.yexcr.2013.12.025. View

Boorstein R, Cummings Jr A, Marenstein D, Chan M, Ma Y, Neubert T . Definitive identification of mammalian 5-hydroxymethyluracil DNA N-glycosylase activity as SMUG1. J Biol Chem. 2001; 276(45):41991-7. DOI: 10.1074/jbc.M106953200. View

Haushalter K, Todd Stukenberg M, Kirschner M, Verdine G . Identification of a new uracil-DNA glycosylase family by expression cloning using synthetic inhibitors. Curr Biol. 1999; 9(4):174-85. DOI: 10.1016/s0960-9822(99)80087-6. View

An Q, Robins P, Lindahl T, Barnes D . 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. Cancer Res. 2007; 67(3):940-5. DOI: 10.1158/0008-5472.CAN-06-2960. View

Ma L, Li G, Wu Z, Meng G . Prognostic significance of let-7b expression in breast cancer and correlation to its target gene of BSG expression. Med Oncol. 2013; 31(1):773. DOI: 10.1007/s12032-013-0773-7. View

Ye F, Wang H, Liu J, Cheng Q, Chen X, Chen H . Association of SMUG1 SNPs in Intron Region and Linkage Disequilibrium with Occurrence of Cervical Carcinoma and HPV Infection in Chinese Population. J Cancer. 2019; 10(1):238-248. PMC: 6329855. DOI: 10.7150/jca.27103. View

Abdel-Fatah T, Perry C, Arora A, Thompson N, Doherty R, Moseley P . Is there a role for base excision repair in estrogen/estrogen receptor-driven breast cancers?. Antioxid Redox Signal. 2014; 21(16):2262-8. PMC: 4620128. DOI: 10.1089/ars.2014.6077. View

10.

Juul M, Bertl J, Guo Q, Nielsen M, Switnicki M, Hornshoj H . Non-coding cancer driver candidates identified with a sample- and position-specific model of the somatic mutation rate. Elife. 2017; 6. PMC: 5440169. DOI: 10.7554/eLife.21778. View

11.

Tinevez J, Perry N, Schindelin J, Hoopes G, Reynolds G, Laplantine E . TrackMate: An open and extensible platform for single-particle tracking. Methods. 2016; 115:80-90. DOI: 10.1016/j.ymeth.2016.09.016. View

12.

Masaoka A, Matsubara M, Hasegawa R, Tanaka T, Kurisu S, Terato H . Mammalian 5-formyluracil-DNA glycosylase. 2. Role of SMUG1 uracil-DNA glycosylase in repair of 5-formyluracil and other oxidized and deaminated base lesions. Biochemistry. 2003; 42(17):5003-12. DOI: 10.1021/bi0273213. View

13.

Vlachos I, Zagganas K, Paraskevopoulou M, Georgakilas G, Karagkouni D, Vergoulis T . DIANA-miRPath v3.0: deciphering microRNA function with experimental support. Nucleic Acids Res. 2015; 43(W1):W460-6. PMC: 4489228. DOI: 10.1093/nar/gkv403. View

14.

Kavli B, Sundheim O, Akbari M, Otterlei M, Nilsen H, Skorpen F . hUNG2 is the major repair enzyme for removal of uracil from U:A matches, U:G mismatches, and U in single-stranded DNA, with hSMUG1 as a broad specificity backup. J Biol Chem. 2002; 277(42):39926-36. DOI: 10.1074/jbc.M207107200. View

15.

Cui J, Gizzi A, Stivers J . Deoxyuridine in DNA has an inhibitory and promutagenic effect on RNA transcription by diverse RNA polymerases. Nucleic Acids Res. 2019; 47(8):4153-4168. PMC: 6486633. DOI: 10.1093/nar/gkz183. View

16.

Pfaffeneder T, Spada F, Wagner M, Brandmayr C, Laube S, Eisen D . Tet oxidizes thymine to 5-hydroxymethyluracil in mouse embryonic stem cell DNA. Nat Chem Biol. 2014; 10(7):574-81. DOI: 10.1038/nchembio.1532. View

17.

Nagaria P, Svilar D, Brown A, Wang X, Sobol R, Wyatt M . SMUG1 but not UNG DNA glycosylase contributes to the cellular response to recovery from 5-fluorouracil induced replication stress. Mutat Res. 2012; 743-744:26-32. PMC: 3616158. DOI: 10.1016/j.mrfmmm.2012.12.001. View

18.

Xie H, Gong Y, Dai J, Wu X, Gu J . Genetic variations in base excision repair pathway and risk of bladder cancer: a case-control study in the United States. Mol Carcinog. 2013; 54(1):50-7. DOI: 10.1002/mc.22073. View

19.

Chirshev E, Oberg K, Ioffe Y, Unternaehrer J . Let-7 as biomarker, prognostic indicator, and therapy for precision medicine in cancer. Clin Transl Med. 2019; 8(1):24. PMC: 6715759. DOI: 10.1186/s40169-019-0240-y. View

20.

Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C . let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007; 131(6):1109-23. DOI: 10.1016/j.cell.2007.10.054. View