SMUG1
Single-strand selective monofunctional uracil DNA glycosylase is an enzyme that in humans is encoded by the SMUG1 gene.[4][5][6] SMUG1 is a glycosylase that removes uracil from single- and double-stranded DNA in nuclear chromatin, thus contributing to base excision repair.[6]
Function
SMUG1 is an important uracil-DNA glycosylases that process uracil in DNA. SMUG1 function is to remove U or its derivatives from DNA. SMUG1 is able to excise uracil from both single- and doubledstranded DNA.[7] Other DNA glycosylases linked to U removal are UNG, TDG and MBD4.[8] Uracil-DNA repair is essential to protect against mutations. Current evidence suggests that UNG and SMUG1 are the major enzymes responsible for the repair of the U:G mispairs.[7][9][10] Uracil is also introduced into DNA as part of antibody gene diversification and its removal is critical to antibody diversification. UNG is known to be the major player in uracil removal but when depleted SMUG1 can provide a backup for UNG in the antibody diversification process.[11][12]
In addition to uracil, SMUG1 removes several pyrimidine oxidation products.[13] and has a specific function to remove the thymine oxidation product 5-hydroxymethyl uracil from DNA.[14]
Role in cancer
Low SMUG1 transcripts can impair DNA repair and thus increase mutation rate, enhance chromosomal instability and promote selection of more malignant clones with aggressive behavior. Loss of SMUG1 was shown to increase cancer predisposition in mice study.[15] In addition low SMUG1 transcripts were shown to be potentially correlated with poor survival and linked to aggressive phenotype in breast cancer.[16] Low SMUG1 expression is also associated with BRCA1, ATM, XRCC1, implying genomic instability in SMUG1 low tumors.[16] Preclinical study where SMUG1 depletion has been shown to results in sensitivity to 5-FU chemotherapy.[17]
Low SMUG1 in gastric cancer, however, were showing the opposite result, promoting cancer survival and resistance to therapy. One possible explanation is that in gastric cancer inflammation is the driver for carcinogenesis and low concentrations of SMUG1 can be beneficial in repairing oxidative base damage (commonly seen in inflammatory environment). Thus SMUG1 might have complex roles in carcinogenesis and act differently based on the type of cancer and its properties.[18]
Role in drug response
5-Fluorouracil (5-FU) is a widely used in the treatment of a range of common cancers that causes DNA damage via two mechanisms. FU is thought to kill cells via the inhibition of thymidylate synthase and also deprive cells of TTP during DNA replication, which leads to the introduction of uracil in DNA causing the fragmentation of newly synthesized DNA. Also, 5-FU is directly incorporated into DNA. UNG and SMUG1 are most likely to tackle the genomic incorporation of uracil and 5-FU during replication. Current research suggests that of SMUG1 but not UNG corresponds to increase in sensitivity to 5-FU. It was suggested that SMUG1 can be potentially used as a predictive biomarkers of drug response and a mechanism for acquired resistance in certain types of tumors.[17][19]
SMUG1 glycosylase is a key enzyme for repairing lesions generated during oxidative base damage. Investigation of SMUG1 expression in gastric cancers showed that overexpressed SMUG1 was correlated with patients’ poor survival. In gastric cancer inflammation is the driver for carcinogenesis. And thus one possible explanation is that cancer cells are under considerable oxidative stress compared to normal cells and unregulation of SMUG1 is essential for the repair of oxidative base damage and survival in cancer cells.[18] In this case elevation of SMUG1 as opposed to depletion can be potentially used as a biomarker for survival.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601".
References
- GRCm38: Ensembl release 89: ENSMUSG00000036061 - Ensembl, May 2017
- "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- Haushalter KA, Todd Stukenberg MW, Kirschner MW, Verdine GL (February 1999). "Identification of a new uracil-DNA glycosylase family by expression cloning using synthetic inhibitors". Current Biology. 9 (4): 174–85. doi:10.1016/S0960-9822(99)80087-6. PMID 10074426.
- Boorstein RJ, Cummings A, Marenstein DR, Chan MK, Ma Y, Neubert TA, Brown SM, Teebor GW (November 2001). "Definitive identification of mammalian 5-hydroxymethyluracil DNA N-glycosylase activity as SMUG1". The Journal of Biological Chemistry. 276 (45): 41991–7. doi:10.1074/jbc.M106953200. PMID 11526119.
- "Entrez Gene: SMUG1 single-strand-selective monofunctional uracil-DNA glycosylase 1".
- Kavli B, Sundheim O, Akbari M, Otterlei M, Nilsen H, Skorpen F, Aas PA, Hagen L, Krokan HE, Slupphaug G (October 2002). "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". The Journal of Biological Chemistry. 277 (42): 39926–36. doi:10.1074/jbc.M207107200. PMID 12161446.
- Krokan HE, Drabløs F, Slupphaug G (December 2002). "Uracil in DNA--occurrence, consequences and repair". Oncogene. 21 (58): 8935–48. doi:10.1038/sj.onc.1205996. PMID 12483510.
- Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, Daly G, Krokan HE, Lindahl T, Barnes DE, Nilsen H, Rosewell I, Robins P, Skjelbred CF, Andersen S, Slupphaug G, Daly G, Krokan HE, Lindahl T, Barnes DE (June 2000). "Uracil-DNA glycosylase (UNG)-deficient mice reveal a primary role of the enzyme during DNA replication". Molecular Cell. 5 (6): 1059–65. doi:10.1016/S1097-2765(00)80271-3. PMID 10912000.
- Kavli B, Andersen S, Otterlei M, Liabakk NB, Imai K, Fischer A, Durandy A, Krokan HE, Slupphaug G (June 2005). "B cells from hyper-IgM patients carrying UNG mutations lack ability to remove uracil from ssDNA and have elevated genomic uracil". The Journal of Experimental Medicine. 201 (12): 2011–21. doi:10.1084/jem.20050042. PMC 2212036. PMID 15967827.
- Di Noia J, Neuberger MS (September 2002). "Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase". Nature. 419 (6902): 43–8. doi:10.1038/nature00981. PMID 12214226.
- Rada C, Di Noia JM, Neuberger MS, Rada C, Di Noia JM, Neuberger MS (October 2004). "Mismatch recognition and uracil excision provide complementary paths to both Ig switching and the A/T-focused phase of somatic mutation". Molecular Cell. 16 (2): 163–71. doi:10.1016/j.molcel.2004.10.011. PMID 15494304.
- Masaoka A, Matsubara M, Hasegawa R, Tanaka T, Kurisu S, Terato H, Ohyama Y, Karino N, Matsuda A, Ide H (May 2003). "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. 42 (17): 5003–12. doi:10.1021/bi0273213. PMID 12718543.
- Boorstein RJ, Cummings A, Marenstein DR, Chan MK, Ma Y, Neubert TA, Brown SM, Teebor GW (November 2001). "Definitive identification of mammalian 5-hydroxymethyluracil DNA N-glycosylase activity as SMUG1". The Journal of Biological Chemistry. 276 (45): 41991–7. doi:10.1074/jbc.M106953200. PMID 11526119.
- Kemmerich K, Dingler FA, Rada C, Neuberger MS (July 2012). "Germline ablation of SMUG1 DNA glycosylase causes loss of 5-hydroxymethyluracil- and UNG-backup uracil-excision activities and increases cancer predisposition of Ung-/-Msh2-/- mice". Nucleic Acids Research. 40 (13): 6016–25. doi:10.1093/nar/gks259. PMC 3401444. PMID 22447450.
- Abdel-Fatah TM, Albarakati N, Bowell L, Agarwal D, Moseley P, Hawkes C, Ball G, Chan S, Ellis IO, Madhusudan S (December 2013). "Single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) deficiency is linked to aggressive breast cancer and predicts response to adjuvant therapy" (PDF). Breast Cancer Research and Treatment. 142 (3): 515–27. doi:10.1007/s10549-013-2769-6. PMID 24253812.
- An Q, Robins P, Lindahl T, Barnes DE (February 2007). "5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity". Cancer Research. 67 (3): 940–5. doi:10.1158/0008-5472.CAN-06-2960. PMID 17283124.
- Abdel-Fatah T, Arora A, Gorguc I, Abbotts R, Beebeejaun S, Storr S, Mohan V, Hawkes C, Soomro I, Lobo DN, Parsons SL, Madhusudan S (June 2013). "Are DNA repair factors promising biomarkers for personalized therapy in gastric cancer?" (PDF). Antioxidants & Redox Signaling. 18 (18): 2392–8. doi:10.1089/ars.2012.4873. PMID 22894650.
- Nagaria P, Svilar D, Brown AR, Wang XH, Sobol RW, Wyatt MD (2013-03-01). "SMUG1 but not UNG DNA glycosylase contributes to the cellular response to recovery from 5-fluorouracil induced replication stress". Mutation Research. SI: DNA Repair and Genetic Instability. 743–744: 26–32. doi:10.1016/j.mrfmmm.2012.12.001. PMC 3616158. PMID 23253900.
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
- Jobert L, Skjeldam HK, Dalhus B, Galashevskaya A, Vågbø CB, Bjørås M, Nilsen H (January 2013). "The human base excision repair enzyme SMUG1 directly interacts with DKC1 and contributes to RNA quality control". Molecular Cell. 49 (2): 339–45. doi:10.1016/j.molcel.2012.11.010. PMID 23246433.
Further reading
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Kavli B, Sundheim O, Akbari M, Otterlei M, Nilsen H, Skorpen F, Aas PA, Hagen L, Krokan HE, Slupphaug G (October 2002). "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". The Journal of Biological Chemistry. 277 (42): 39926–36. doi:10.1074/jbc.M207107200. PMID 12161446.
- Masaoka A, Matsubara M, Hasegawa R, Tanaka T, Kurisu S, Terato H, Ohyama Y, Karino N, Matsuda A, Ide H (May 2003). "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. 42 (17): 5003–12. doi:10.1021/bi0273213. PMID 12718543.
- Wibley JE, Waters TR, Haushalter K, Verdine GL, Pearl LH (June 2003). "Structure and specificity of the vertebrate anti-mutator uracil-DNA glycosylase SMUG1". Molecular Cell. 11 (6): 1647–59. doi:10.1016/S1097-2765(03)00235-1. PMID 12820976.
- Matsubara M, Tanaka T, Terato H, Ohmae E, Izumi S, Katayanagi K, Ide H (2004). "Mutational analysis of the damage-recognition and catalytic mechanism of human SMUG1 DNA glycosylase". Nucleic Acids Research. 32 (17): 5291–302. doi:10.1093/nar/gkh859. PMC 521670. PMID 15466595.
- Schröfelbauer B, Yu Q, Zeitlin SG, Landau NR (September 2005). "Human immunodeficiency virus type 1 Vpr induces the degradation of the UNG and SMUG uracil-DNA glycosylases". Journal of Virology. 79 (17): 10978–87. doi:10.1128/JVI.79.17.10978-10987.2005. PMC 1193627. PMID 16103149.
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
- Di Noia JM, Rada C, Neuberger MS (February 2006). "SMUG1 is able to excise uracil from immunoglobulin genes: insight into mutation versus repair". The EMBO Journal. 25 (3): 585–95. doi:10.1038/sj.emboj.7600939. PMC 1383525. PMID 16407970.
- Broderick P, Bagratuni T, Vijayakrishnan J, Lubbe S, Chandler I, Houlston RS (2006). "Evaluation of NTHL1, NEIL1, NEIL2, MPG, TDG, UNG and SMUG1 genes in familial colorectal cancer predisposition". BMC Cancer. 6: 243. doi:10.1186/1471-2407-6-243. PMC 1624846. PMID 17029639.
- Matsubara M, Tanaka T, Terato H, Ide H (2005). "Action mechanism of human SMUG1 uracil-DNA glycosylase". Nucleic Acids Symposium Series. 49 (49): 295–6. doi:10.1093/nass/49.1.295. PMID 17150750.
- Pettersen HS, Sundheim O, Gilljam KM, Slupphaug G, Krokan HE, Kavli B (2007). "Uracil-DNA glycosylases SMUG1 and UNG2 coordinate the initial steps of base excision repair by distinct mechanisms". Nucleic Acids Research. 35 (12): 3879–92. doi:10.1093/nar/gkm372. PMC 1919486. PMID 17537817.