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Curia MC, Catalano T, Aceto GM. MUTYH: Not just polyposis. World J Clin Oncol 2020; 11:428-449. [PMID: 32821650 PMCID: PMC7407923 DOI: 10.5306/wjco.v11.i7.428] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/08/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
MUTYH is a base excision repair enzyme, it plays a crucial role in the correction of DNA errors from guanine oxidation and may be considered a cell protective factor. In humans it is an adenine DNA glycosylase that removes adenine misincorporated in 7,8-dihydro-8-oxoguanine (8-oxoG) pairs, inducing G:C to T:A transversions. MUTYH functionally cooperates with OGG1 that eliminates 8-oxodG derived from excessive reactive oxygen species production. MUTYH mutations have been linked to MUTYH associated polyposis syndrome (MAP), an autosomal recessive disorder characterized by multiple colorectal adenomas. MAP patients show a greatly increased lifetime risk for gastrointestinal cancers. The cancer risk in mono-allelic carriers associated with one MUTYH mutant allele is controversial and it remains to be clarified whether the altered functions of this protein may have a pathophysiological involvement in other diseases besides familial gastrointestinal diseases. This review evaluates the role of MUTYH, focusing on current studies of human neoplastic and non-neoplastic diseases different to colon polyposis and colorectal cancer. This will provide novel insights into the understanding of the molecular basis underlying MUTYH-related pathogenesis. Furthermore, we describe the association between MUTYH single nucleotide polymorphisms (SNPs) and different cancer and non-cancer diseases. We address the utility to increase our knowledge regarding MUTYH in the light of recent advances in the literature with the aim of a better understanding of the potential for identifying new therapeutic targets. Considering the multiple functions and interactions of MUTYH protein, its involvement in pathologies based on oxidative stress damage could be hypothesized. Although the development of extraintestinal cancer in MUTYH heterozygotes is not completely defined, the risk for malignancies of the duodenum, ovary, and bladder is also increased as well as the onset of benign and malignant endocrine tumors. The presence of MUTYH pathogenic variants is an independent predictor of poor prognosis in sporadic gastric cancer and in salivary gland secretory carcinoma, while its inhibition has been shown to reduce the survival of pancreatic ductal adenocarcinoma cells. Furthermore, some MUTYH SNPs have been associated with lung, hepatocellular and cervical cancer risk. An additional role of MUTYH seems to contribute to the prevention of numerous other disorders with an inflammatory/degenerative basis, including neurological and ocular diseases. Finally, it is interesting to note that MUTYH could be a new therapeutic target and future studies will shed light on its specific functions in the prevention of diseases and in the improvement of the chemo-sensitivity of cancer cells.
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Affiliation(s)
- Maria Cristina Curia
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Via Consolare Valeria 98125, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d'Annunzio” University of Chieti-Pescara, Chieti, Via dei Vestini 66100, Italy
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Boldinova EO, Khairullin RF, Makarova AV, Zharkov DO. Isoforms of Base Excision Repair Enzymes Produced by Alternative Splicing. Int J Mol Sci 2019; 20:ijms20133279. [PMID: 31277343 PMCID: PMC6651865 DOI: 10.3390/ijms20133279] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 06/29/2019] [Accepted: 07/02/2019] [Indexed: 02/07/2023] Open
Abstract
Transcripts of many enzymes involved in base excision repair (BER) undergo extensive alternative splicing, but functions of the corresponding alternative splice variants remain largely unexplored. In this review, we cover the studies describing the common alternatively spliced isoforms and disease-associated variants of DNA glycosylases, AP-endonuclease 1, and DNA polymerase beta. We also discuss the roles of alternative splicing in the regulation of their expression, catalytic activities, and intracellular transport.
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Affiliation(s)
| | - Rafil F Khairullin
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 9 Parizhskoy Kommuny Str., 420012 Kazan, Russia
| | - Alena V Makarova
- RAS Institute of Molecular Genetics, 2 Kurchatova Sq., 123182 Moscow, Russia.
| | - Dmitry O Zharkov
- Novosibirsk State University, 1 Pirogova St., 630090 Novosibirsk, Russia.
- SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., 630090 Novosibirsk, Russia.
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3
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Variation in MUTYH expression in Arabian horses with Cerebellar Abiotrophy. Brain Res 2017; 1678:330-336. [PMID: 29103988 DOI: 10.1016/j.brainres.2017.10.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 10/24/2017] [Accepted: 10/29/2017] [Indexed: 12/17/2022]
Abstract
Cerebellar Abiotrophy (CA) is a neurodegenerative disease in Arabian horses affecting the cerebellum, more specifically the Purkinje neurons. Although CA occurs in several domestic species, CA in Arabian horses is unique in that a single nucleotide polymorphism (SNP) has been associated with the disease. Total RNA sequencing (RNA-seq) was performed on CA-affected horses to address the molecular mechanism underlying the disease. This research expands upon the RNA-seq work by measuring the impact of the CA-associated SNP on the candidate gene MutY homolog (MUTYH) and its regulation, isoform-specific expression and protein localization. We hypothesized that the CA-associated SNP compromises the promoter region of MUTYH, leading to differential expression of its isoforms. Our research demonstrates that the CA-associated SNP introduces a new binding site for a novel transcription factor (Myelin Transcription Factor-1 Like protein, MYT1L). In addition, CA-affected horses show differential expression of a specific isoform of MUTYH as well as different localization in the Purkinje and granular neurons of the cerebellum.
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Kunrath-Lima M, Repolês BM, Alves CL, Furtado C, Rajão MA, Macedo AM, Franco GR, Pena SDJ, Valenzuela L, Wisnovsky S, Kelley SO, Galanti N, Cabrera G, Machado CR. Characterization of Trypanosoma cruzi MutY DNA glycosylase ortholog and its role in oxidative stress response. INFECTION GENETICS AND EVOLUTION 2017; 55:332-342. [PMID: 28970112 DOI: 10.1016/j.meegid.2017.09.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 09/25/2017] [Accepted: 09/26/2017] [Indexed: 12/11/2022]
Abstract
Trypanosoma cruzi is a protozoan parasite and the causative agent of Chagas disease. Like most living organisms, it is susceptible to oxidative stress, and must adapt to distinct environments. Hence, DNA repair is essential for its survival and the persistence of infection. Therefore, we studied whether T. cruzi has a homolog counterpart of the MutY enzyme (TcMYH), important in the DNA Base Excision Repair (BER) mechanism. Analysis of T. cruzi genome database showed that this parasite has a putative MutY DNA glycosylase sequence. We performed heterologous complementation assays using this genomic sequence. TcMYH complemented the Escherichia coli MutY- strain, reducing the mutation rate to a level similar to wild type. In in vitro assays, TcMYH was able to remove an adenine that was opposite to 8-oxoguanine. We have also constructed a T. cruzi lineage that overexpresses MYH. Although in standard conditions this lineage has similar growth to control cells, the overexpressor is more sensitive to hydrogen peroxide and glucose oxidase than the control, probably due to accumulation of AP sites in its DNA. Localization experiments with GFP-fused TcMYH showed this enzyme is present in both nucleus and mitochondrion. QPCR and MtOX results reinforce the presence and function of TcMYH in these two organelles. Our data suggest T. cruzi has a functional MYH DNA glycosylase, which participates in nuclear and mitochondrial DNA Base Excision Repair.
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Affiliation(s)
- Marianna Kunrath-Lima
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Bruno Marçal Repolês
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Ceres Luciana Alves
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Carolina Furtado
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Matheus Andrade Rajão
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Andrea Mara Macedo
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil
| | - Glória Regina Franco
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil.
| | - Sérgio Danilo Junho Pena
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil.
| | - Lucía Valenzuela
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile
| | - Simon Wisnovsky
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Shana O Kelley
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Norbel Galanti
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
| | - Gonzalo Cabrera
- Programa de Biología Celular y Molecular, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
| | - Carlos Renato Machado
- Departamento de Bioquímica e Imunologia, ICB, Universidade Federal de Minas Gerais, Av. Antônio Carlos, 6627, Caixa Postal 486, Belo Horizonte 30161-970, MG, Brazil.
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Scott EY, Penedo MCT, Murray JD, Finno CJ. Defining Trends in Global Gene Expression in Arabian Horses with Cerebellar Abiotrophy. CEREBELLUM (LONDON, ENGLAND) 2017; 16:462-472. [PMID: 27709457 PMCID: PMC5336519 DOI: 10.1007/s12311-016-0823-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease that affects the Purkinje neurons of the cerebellum and causes ataxia in Arabian foals. Signs of CA are typically first recognized either at birth to any time up to 6 months of age. CA is inherited as an autosomal recessive trait and is associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (13074277G>A), located in the fourth exon of TOE1 and in proximity to MUTYH on the antisense strand. We hypothesize that unraveling the functional consequences of the CA SNP using RNA-seq will elucidate the molecular pathways underlying the CA phenotype. RNA-seq (100 bp PE strand-specific) was performed in cerebellar tissue from four CA-affected and five age-matched unaffected horses. Three pipelines for differential gene expression (DE) analysis were used (Tophat2/Cuffdiff2, Kallisto/EdgeR, and Kallisto/Sleuth) with 151 significant DE genes identified by all three pipelines in CA-affected horses. TOE1 (Log2(foldchange) = 0.92, p = 0.66) and MUTYH (Log2(foldchange) = 1.13, p = 0.66) were not differentially expressed. Among the major pathways that were differentially expressed, genes associated with calcium homeostasis and specifically expressed in Purkinje neurons, CALB1 (Log2(foldchange) = -1.7, p < 0.01) and CA8 (Log2(foldchange) = -0.97, p < 0.01), were significantly down-regulated, confirming loss of Purkinje neurons. There was also a significant up-regulation of markers for microglial phagocytosis, TYROBP (Log2(foldchange) = 1.99, p < 0.01) and TREM2 (Log2(foldchange) = 2.02, p < 0.01). These findings reaffirm a loss of Purkinje neurons in CA-affected horses along with a potential secondary loss of granular neurons and activation of microglial cells.
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Affiliation(s)
- E Y Scott
- Department of Animal Science, University of California, Davis, USA
| | - M C T Penedo
- Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California, Davis, USA
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, USA
| | - J D Murray
- Department of Animal Science, University of California, Davis, USA.
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, USA.
| | - C J Finno
- Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, USA.
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Torgasheva NA, Menzorova NI, Sibirtsev YT, Rasskazov VA, Zharkov DO, Nevinsky GA. Base excision DNA repair in the embryonic development of the sea urchin, Strongylocentrotus intermedius. MOLECULAR BIOSYSTEMS 2016; 12:2247-56. [PMID: 27158700 DOI: 10.1039/c5mb00906e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In actively proliferating cells, such as the cells of the developing embryo, DNA repair is crucial for preventing the accumulation of mutations and synchronizing cell division. Sea urchin embryo growth was analyzed and extracts were prepared. The relative activity of DNA polymerase, apurinic/apyrimidinic (AP) endonuclease, uracil-DNA glycosylase, 8-oxoguanine-DNA glycosylase, and other glycosylases was analyzed using specific oligonucleotide substrates of these enzymes; the reaction products were resolved by denaturing 20% polyacrylamide gel electrophoresis. We have characterized the profile of several key base excision repair activities in the developing embryos (2 blastomers to mid-pluteus) of the grey sea urchin, Strongylocentrotus intermedius. The uracil-DNA glycosylase specific activity sharply increased after blastula hatching, whereas the specific activity of 8-oxoguanine-DNA glycosylase steadily decreased over the course of the development. The AP-endonuclease activity gradually increased but dropped at the last sampled stage (mid-pluteus 2). The DNA polymerase activity was high at the first cleavage division and then quickly decreased, showing a transient peak at blastula hatching. It seems that the developing sea urchin embryo encounters different DNA-damaging factors early in development within the protective envelope and later as a free-floating larva, with hatching necessitating adaptation to the shift in genotoxic stress conditions. No correlation was observed between the dynamics of the enzyme activities and published gene expression data from developing congeneric species, S. purpuratus. The results suggest that base excision repair enzymes may be regulated in the sea urchin embryos at the level of covalent modification or protein stability.
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Affiliation(s)
- Natalya A Torgasheva
- Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentieva Ave., Novosibirsk 630090, Russia. and Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia
| | - Natalya I Menzorova
- G. B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, 159 100 let Vladivostoku Ave., Vladivostok 690022, Russia
| | - Yurii T Sibirtsev
- G. B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, 159 100 let Vladivostoku Ave., Vladivostok 690022, Russia
| | - Valery A Rasskazov
- G. B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, 159 100 let Vladivostoku Ave., Vladivostok 690022, Russia
| | - Dmitry O Zharkov
- Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentieva Ave., Novosibirsk 630090, Russia. and Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia
| | - Georgy A Nevinsky
- Institute of Chemical Biology and Fundamental Medicine SB RAS, 8 Lavrentieva Ave., Novosibirsk 630090, Russia. and Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia
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7
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Bosshard M, Markkanen E, van Loon B. Base excision repair in physiology and pathology of the central nervous system. Int J Mol Sci 2012. [PMID: 23203191 PMCID: PMC3546685 DOI: 10.3390/ijms131216172] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Relatively low levels of antioxidant enzymes and high oxygen metabolism result in formation of numerous oxidized DNA lesions in the tissues of the central nervous system. Accumulation of damage in the DNA, due to continuous genotoxic stress, has been linked to both aging and the development of various neurodegenerative disorders. Different DNA repair pathways have evolved to successfully act on damaged DNA and prevent genomic instability. The predominant and essential DNA repair pathway for the removal of small DNA base lesions is base excision repair (BER). In this review we will discuss the current knowledge on the involvement of BER proteins in the maintenance of genetic stability in different brain regions and how changes in the levels of these proteins contribute to aging and the onset of neurodegenerative disorders.
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Affiliation(s)
- Matthias Bosshard
- Institute for Veterinary Biochemistry and Molecular Biology, University of Zürich-Irchel, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
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Pachkowski BF, Guyton KZ, Sonawane B. DNA repair during in utero development: A review of the current state of knowledge, research needs, and potential application in risk assessment. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2011; 728:35-46. [DOI: 10.1016/j.mrrev.2011.05.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Revised: 05/29/2011] [Accepted: 05/31/2011] [Indexed: 10/18/2022]
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Brault LS, Cooper CA, Famula TR, Murray JD, Penedo MCT. Mapping of equine cerebellar abiotrophy to ECA2 and identification of a potential causative mutation affecting expression of MUTYH. Genomics 2011; 97:121-9. [DOI: 10.1016/j.ygeno.2010.11.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 11/19/2010] [Accepted: 11/20/2010] [Indexed: 11/27/2022]
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Wei W, Englander EW. DNA polymerase beta-catalyzed-PCNA independent long patch base excision repair synthesis: a mechanism for repair of oxidatively damaged DNA ends in post-mitotic brain. J Neurochem 2008; 107:734-44. [PMID: 18752643 PMCID: PMC2967482 DOI: 10.1111/j.1471-4159.2008.05644.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Oxidative DNA damage incidental to normal respiratory metabolism poses a particular threat to genomes of highly metabolic-long lived cells. We show that post-mitotic brain has capacity to repair oxidatively damaged DNA ends, which are targets of the long patch (LP) base excision repair (BER) subpathway. LP-BER relies, in part, on proteins associated with DNA replication, including proliferating cell nuclear antigen and is inherent to proliferating cells. Nonetheless, repair products are generated with brain extracts, albeit at slow rates, in the case of 5'-DNA ends modeled with tetrahydrofuran (THF). THF at this position is refractory to DNA polymerase beta 5'-deoxyribose 5-phosphate lyase activity and drives repair into the LP-BER subpathway. Comparison of repair of 5'-THF-blocked termini in the post-mitotic rat brain and proliferative intestinal mucosa, revealed that in mucosa, resolution of damaged 5'-termini is accompanied by formation of larger repair products. In contrast, adducts targeted by the single nucleotide BER are proficiently repaired with both extracts. Our findings reveal mechanistic differences in BER processes selective for the brain versus proliferative tissues. The differences highlight the physiological relevance of the recently proposed 'Hit and Run' mechanism of alternating cleavage/synthesis steps, in the proliferating cell nuclear antigen-independent LP-BER process.
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Affiliation(s)
- Wei Wei
- Department of Surgery, University of Texas Medical Branch, Galveston, Texas 77555-1220, USA
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11
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Englander EW. Brain capacity for repair of oxidatively damaged DNA and preservation of neuronal function. Mech Ageing Dev 2008; 129:475-82. [PMID: 18374390 PMCID: PMC2519888 DOI: 10.1016/j.mad.2008.02.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2007] [Revised: 01/23/2008] [Accepted: 02/07/2008] [Indexed: 11/20/2022]
Abstract
Accumulation of oxidative DNA damage in the human brain has been implicated in etiologies of post-traumatic and age-associated declines in neuronal function. In neurons, because of high metabolic rates and prolonged life span, exposure to free radicals is intense and risk for accumulation of damaged DNA is amplified. While data indicate that the brain is equipped to repair nuclear and mitochondrial DNA, it is unclear whether repair is executed by distinct subsets of the DNA-repair machinery. Likewise, there are no firm assessments of brain capacity for accurate DNA repair under normal and more so compromised conditions. Consequently, the scope of DNA repair in the brain and the impact of resolution of oxidative lesions on neuronal survival and function remain largely unknown. This review considers evidences for brain levels and activities of the base excision repair (BER) pathway in the context of newly available, comprehensive in situ hybridization analyses of genes encoding repair enzymes. These analyses suggest that not all subsets of BER are equally represented in the brain. Because BER is the major repair process for oxidatively damaged DNA, to what extent parsimonious BER may contribute to development of neuronal dysfunction and brain injury under compromised conditions, is discussed.
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Affiliation(s)
- Ella W Englander
- Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-1220, USA.
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12
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Xu G, Herzig M, Rotrekl V, Walter CA. Base excision repair, aging and health span. Mech Ageing Dev 2008; 129:366-82. [PMID: 18423806 PMCID: PMC2526234 DOI: 10.1016/j.mad.2008.03.001] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2007] [Revised: 02/28/2008] [Accepted: 03/05/2008] [Indexed: 12/18/2022]
Abstract
DNA damage and mutagenesis are suggested to contribute to aging through their ability to mediate cellular dysfunction. The base excision repair (BER) pathway ameliorates a large number of DNA lesions that arise spontaneously. Many of these lesions are reported to increase with age. Oxidized guanine, repaired largely via base excision repair, is particularly well studied and shown to increase with age. Spontaneous mutant frequencies also increase with age which suggests that mutagenesis may contribute to aging. It is widely accepted that genetic instability contributes to age-related occurrences of cancer and potentially other age-related pathologies. BER activity decreases with age in multiple tissues. The specific BER protein that appears to limit activity varies among tissues. DNA polymerase-beta is reduced in brain from aged mice and rats while AP endonuclease is reduced in spermatogenic cells obtained from old mice. The differences in proteins that appear to limit BER activity among tissues may represent true tissue-specific differences in activity or may be due to differences in techniques, environmental conditions or other unidentified differences among the experimental approaches. Much remains to be addressed concerning the potential role of BER in aging and age-related health span.
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Affiliation(s)
- Guogang Xu
- Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
| | - Maryanne Herzig
- Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
| | - Vladimir Rotrekl
- Institute of Experimental Medicine, Department of Molecular Embryology, Masaryk University, Faculty of Medicine, Department of Biology, Kamenice 5, Building A6, 62500 Brno, Czech Republic
| | - Christi A. Walter
- Department of Cellular & Structural Biology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900
- South Texas Veteran’s Health Care System, 7400 Merton Minter Blvd, San Antonio, TX 78229
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Chen L, Lee HM, Greeley GH, Englander EW. Accumulation of oxidatively generated DNA damage in the brain: a mechanism of neurotoxicity. Free Radic Biol Med 2007; 42:385-93. [PMID: 17210451 PMCID: PMC2049091 DOI: 10.1016/j.freeradbiomed.2006.11.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2006] [Revised: 11/02/2006] [Accepted: 11/06/2006] [Indexed: 10/23/2022]
Abstract
Unrepaired or erroneously repaired DNA lesions drive genomic instability and contribute to cellular and organ decline. Since delayed neuropathologies are common in survivors of smoke inhalation injuries, we asked whether the integrity of brain DNA might be compromised by acute exposure to combustion smoke. Although many studies demonstrate that the brain is equipped to repair oxidatively damaged DNA, to date, the capacity for accurate DNA repair under conditions of disrupted oxygenation and oxidative stress has not been defined. We show that DNA adducts detectable by their ability to block PCR amplification form in the rat hippocampus after acute exposure to smoke. To identify the different types of adducts and to dissect their temporal formation and repair profiles in vivo in the brain, we used DNA-modifying enzymes to convert specific adducts into strand breaks prior to PCR amplification. Using this strategy, we detected formation of oxidative DNA adducts early on after smoke inhalation, while mismatched bases emerged at the later recovery times, potentially due to an erroneous DNA repair process. Erroneous repair can be mutagenic and because the initial smoke-induced oxidative damage to DNA is extensive, compromised fidelity of DNA repair may underlie neurotoxicity and contribute to delayed death of hippocampal neurons.
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Affiliation(s)
- Liuji Chen
- Department of Surgery, University of Texas Medical Branch
- Shriners Hospitals for Children, Galveston, Texas
| | - Heung M Lee
- Department of Surgery, University of Texas Medical Branch
- Shriners Hospitals for Children, Galveston, Texas
| | | | - Ella W Englander
- Department of Surgery, University of Texas Medical Branch
- Shriners Hospitals for Children, Galveston, Texas
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Wang G, Qi X, Wei W, Englander EW, Greeley GH. Characterization of the 5'‐regulatory regions of the rat and human apelin genes and regulation of breast apelin by USF. FASEB J 2006; 20:2639-41. [PMID: 17060400 DOI: 10.1096/fj.06-6315fje] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Apelin, a peptide widely expressed in the body, is the endogenous ligand for the APJ receptor. To investigate how the apelin gene is regulated transcriptionally, we cloned and characterized approximately 3000 and approximately 4000 bp 5'-upstream fragments of the rat and human apelin genes. Putative CAAT-like box, but not TATA-box sites were identified. The rat (-207/-1 bp) and human (-100/+74 bp) core promoter sequences contain putative binding sites for upstream stimulatory factor (USF)-1/-2. Mutagenesis and overexpression assays showed that USF up-regulates basal and inducible apelin transcription. EMSA and supershift experiments indicated binding of USF-1/-2 to the rat (-114/-109 bp) and human (-84/-79 bp) apelin promoters. ChIP experiments show that USF is recruited to the putative USF binding site in the human apelin promoter in cultured breast cells. In concert with increased breast apelin expression during pregnancy and lactation in rats, EMSAs demonstrate an elevated binding of pregnant and lactating rat breast nuclear proteins to a consensus USF oligonucleotide. In vivo ChIP assays verified increased USF binding to the apelin promoter in breast of lactating rats. Together, our findings show that USF exerts a stimulatory role in regulation of breast apelin expression during pregnancy and lactation.
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Affiliation(s)
- Guiyun Wang
- Department of Surgery, University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77555, USA
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Wilson DM, McNeill DR. Base excision repair and the central nervous system. Neuroscience 2006; 145:1187-200. [PMID: 16934943 DOI: 10.1016/j.neuroscience.2006.07.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2006] [Revised: 07/10/2006] [Accepted: 07/14/2006] [Indexed: 12/18/2022]
Abstract
Reactive oxygen species generated during normal cellular metabolism react with lipids, proteins, and nucleic acid. Evidence indicates that the accumulation of oxidative damage results in cellular dysfunction or deterioration. In particular, oxidative DNA damage can induce mutagenic replicative outcomes, leading to altered cellular function and/or cellular transformation. Additionally, oxidative DNA modifications can block essential biological processes, namely replication and transcription, triggering cell death responses. The major pathway responsible for removing oxidative DNA damage and restoring the integrity of the genome is base excision repair (BER). We highlight herein what is known about BER protein function(s) in the CNS, which in cooperation with the peripheral nervous system operates to control physical responses, motor coordination, and brain operation. Moreover, we describe evidence indicating that defective BER processing can promote post-mitotic (i.e. non-dividing) neuronal cell death and neurodegenerative disease. The focus of the review is on the core mammalian BER participants, i.e. the DNA glycosylases, AP endonuclease 1, DNA polymerase beta, X-ray cross-complementing 1, and the DNA ligases.
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Affiliation(s)
- D M Wilson
- Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
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Takao M, Yasui A. DNA repair initiated by glycosylases in the nucleus and mitochondria of mammalian cells; how our cells respond to a flood of oxidative DNA damage. ACTA ACUST UNITED AC 2005. [DOI: 10.1016/j.descs.2005.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Englander EW, Ma H. Differential modulation of base excision repair activities during brain ontogeny: implications for repair of transcribed DNA. Mech Ageing Dev 2005; 127:64-9. [PMID: 16257035 DOI: 10.1016/j.mad.2005.09.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2005] [Revised: 09/20/2005] [Accepted: 09/20/2005] [Indexed: 11/17/2022]
Abstract
DNA repair sustains fidelity of genomic replication in proliferating cells and integrity of transcribed sequences in postmitotic tissues. The repair process is critical in the brain, because high oxygen consumption exacerbates the risk for accumulation of oxidative DNA lesions in postmitotic neurons. Most oxidative DNA damage is repaired by the base excision repair (BER) pathway, which is initiated by specialized DNA glycosylases. Because the newly discovered Nei-like mammalian DNA glycosylases (NEIL1/2) proficiently excise oxidized bases from bubble structured DNA, it was suggested that NEILs favor repair of transcribed or replicated DNA. In addition, since NEILs generate 3'-phosphate termini, which are poor targets for AP endonuclease (APE1), it was proposed that APE1-dependent and independent BER sub-pathways exist in mammalian cells. We measured expression and activities of BER enzymes during brain ontogeny, i.e., during a physiologic transition from proliferative to postmitotic differentiated state. While a subset of BER enzymes, exhibited declining expression and excision activities, expression of NEIL1 and NEIL2 glycosylases increased during brain development. Furthermore, the capacity for excision of 5-hydroxyuracil from bubble structured DNA was retained in the mature rat brain suggesting a role for NEIL glycosylases in maintaining the integrity of transcribed DNA in postmitotic brain.
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Affiliation(s)
- Ella W Englander
- Department of Surgery, The University of Texas Medical Branch, Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550, USA.
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