DNA repair deficiency in neurodegeneration
Highlights
► Neurological disease is a major symptom of genomic instability disorders. ► Deficient DNA repair is linked to progressive neurodegeneration. ► Several hereditary ataxia disorders are characterized by defective DNA repair. ► Mitochondrial DNA damage is implicated in the age-associated Alzheimer's disease. ► Neurodegeneration is a feature of the premature aging disorder Werner syndrome.
Introduction
Amongst the fundamental processes, crucial for viability of organisms, including humans, are appropriate cellular signaling responses to DNA damage and the ability to repair such damage. Our cells are constantly exposed to DNA damage caused by endogenous sources such as reactive oxygen species and exogenous sources such as mutagens and radiation. To protect against this damage all cells have various DNA repair pathways. The four major pathways for repairing damage to bases are nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and double-strand break repair (DSBR) (Fig. 1). NER excises bulky helix-distorting DNA lesions and BER repairs damage to a single nucleotide base, whereas MMR corrects mismatches of the normal bases; such as failure to maintain normal Watson–Crick base pairing. Breakage of the DNA backbone also occurs, either in the form of a single-strand break (SSB) or a double-strand break (DSB). SSBs are handled by the BER pathway. The repair of DNA DSBs involves one of two mechanisms: non-homologous end-joining (NHEJ) or homologous recombination (HR). NHEJ directly joins the broken ends, whereas HR uses the intact sister chromatid as a template for repair. In addition, a type of repair termed direct reversal (DR) can reverse some forms of base damage without removing the base. Translesion DNA synthesis (TLS) uses specialized DNA polymerases to replicate past lesions in the DNA, which although more error-prone than BER, NER and MMR, may reduce the immediate danger of DSBs (Prakash and Prakash, 2002).
Deficiencies in DNA repair pathways can result in reduced stability of the cellular chromosomes which in turn can lead to mutagenesis, cellular dysfunction and aberrant phenotypes. Such genomic instability would be expected to potentially increase the risk of cancer, and indeed several hereditary DNA repair deficiency diseases (e.g. Xeroderma Pigmentosum are associated with increased cancer risk). Another major clinical feature of such deficiencies is neurological disease, and accordingly, DNA repair deficiencies are implicated in various diseases that feature progressive neurodegeneration. In the central nervous system (CNS), higher levels of DNA damage either due to increased exposure to damaging agents and/or defective repair of DNA, can lead to pronounced neuropathology. The brain consists largely of non-proliferative neuronal cells and is therefore particularly vulnerable to defective DNA repair that would lead to “accumulation” (more accurately, a greater steady-state level) of unrepaired DNA lesions. These DNA lesions have been proposed to be the cause of the neuropathology observed in several neurodegenerative disorders.
Progressive neurodegeneration occurs when the loss of neuronal structure or function leads to a decline in the number of neurons due to apoptotic cell death. The most consistent risk factor for developing a progressive neurodegenerative disease is aging. With age often comes a decline in brain volume and function, which similarly to neurodegenerative disease can be attributable to the permanent loss of neurons (Brazel and Rao, 2004). The “free radical theory of aging” hypothesizes that accumulation of unrepaired oxidative damage leads to the cellular decline and associated age-related deterioration (Harman, 1981). Considerable circumstantial evidence supports the role of oxidative damage in the aging process (Balaban et al., 2005, Bokov et al., 2004, Golden et al., 2002, Sinclair, 2005), and neurons have very high rates of oxygen metabolism. In view of this it has been suggested that deficiencies in the repair of oxidative DNA damage with aging, correlates with the cognitive decline and neurodegenerative diseases that are more prominent in the aged population (Weissman et al., 2007a). Mitochondria, the main cellular energy generators, are vital for proper neuronal function and survival, and their dysfunction have been linked to neurodegeneration. In addition, it has been suggested by the “mitochondrial theory of aging” that accumulation of mitochondrial damage is the cause of the normal aging process (Harman, 1972).
In this review, we present an overview of the current understanding of the molecular basis for neuronal DNA repair deficiencies associated with neurodegeneration. This will be done by exploring the evidence gained from the study of both inherited and age-associated neurodegenerative diseases. Included are brief descriptions with illustrations of various pathways of DNA repair that we hope will be helpful to readers not already intimately familiar with these important cellular pathways.
Section snippets
Nucleotide excision repair (NER)
Damage from ultraviolet (UV) radiation and reactive oxygen species can generate helix-distorting DNA lesions. The DNA repair process responsible for removing such lesions is the nucleotide excision repair (NER) pathway. NER is a highly conserved and versatile multistep pathway capable of repairing lesions such as UV-induced cyclobutane pyrimidine dimers and 6–4 photoproducts, intra-strand cross-links (Niedernhofer et al., 2004), DNA-protein cross-links (Nouspikel, 2008) and some DNA adducts
Base excision repair (BER)
DNA is inherently unstable due to spontaneous hydrolytic decay and due to modification by both endogenous and exogenous alkylating agents (Lindahl, 1993). In addition reactive oxygen species (ROS), such as the highly reactive hydroxyl radical (•OH), superoxide anion (O2•−) and hydrogen peroxide (H2O2) are generated as a result of normal cellular metabolism. ROS is genotoxic and capable of damaging DNA by generating various oxidative DNA lesions with base or sugar damage (Evans et al., 2004,
Mismatch repair (MMR)
DNA mismatch repair (MMR) is a highly conserved pathway that removes base–base mismatches and insertion-deletion loops that arise during DNA replication and recombination, thereby improving the fidelity of replication 50–1000-fold (Hsieh and Yamane, 2008, Jiricny, 2006). Base–base mismatches are created when errors escape from the proofreading function of DNA polymerases. Insertion-deletion loops arise when primer and template strand in a microsatellite dissociate and re-anneal incorrectly,
Single-strand break repair (SSBR)
SSBs are some of the most common lesions found in chromosomal DNA and they can arise in two different ways: (i) indirectly, via enzymatic cleavage of the phosphodiester backbone. Cleavage occurs during BER of oxidative base damage generated by the attack of ROS (Connelly and Leach, 2004), and also during DNA topoisomerase I (TOP1) activity (Pommier et al., 2003). (ii) Directly, induced by the oxidative damage generated by the attack of ROS such as •OH, O2•− and H2O2, or by ionizing radiation.
Double-strand break repair (DSBR)
One of the most toxic and mutagenic lesions is the DNA double-strand break (DSB), as chromosomal breakage may result in an extreme loss of genetic integrity. DSBs can be induced by exogenous sources, such as ionizing radiation and exposure to genotoxic compounds that directly or indirectly damage DNA. DSBs can also be induced by endogenous sources, such as the ROS generated by cellular metabolism, replication fork collapse during DNA replication and repair events, and during meiotic
Mitochondria and neurons
Mitochondria are membrane-enclosed organelles that generate most of the ATP supply in eukaryotic cells, including neurons. To generate ATP high-energy electrons must be transported through the electron transport chain at the inner mitochondrial membrane. This process leads to the generation of ROS when high-energy electrons react with O2 to form O2•, which in turn leads to generation of H2O2 and •OH. While the mitochondria have various antioxidant enzymes to deactivate these highly reactive
Human RecQ helicases
Helicases are ATP-hydrolysis powered motor proteins that separate the two complementary strands of nucleic acid duplexes. Humans posses five distinct DNA helicases of the RecQ family: WRN, BLM, RECQ1, RECQ4 and RECQ5 (van Brabant et al., 2000). Human RecQ helicases are active in replication, recombination, DNA repair and possibly transcription, chromatin structure regulation and telomere maintenance (Bohr, 2008). These functions provide the RecQ helicases with a key role in maintaining genomic
Conclusion
The neurodegenerative diseases examined in this review highlight the importance of DNA repair in maintaining genomic integrity in the CNS, and implicates DNA damage and DNA repair deficiency in the aging of the brain. Much work still needs to be done to better understand the role of DNA repair enzymes and pathways in neurons. In particular, it would be of great interest to determine and clarify if certain neuronal subpopulations are more vulnerable to the effects of DNA repair deficiencies
Acknowledgements
We thank members of the Laboratory for DNA repair and Aging, Dept Molecular Biology, Aarhus University, Denmark and members of the Laboratory of Molecular Gerontology, NIA-NIH (Baltimore, MD) – especially Deborah Croteau for critically reading the manuscript.
D.K. Jeppesen was supported by the Danish Cancer Society and part of this work was supported by a grant from The Velux Foundation to the Danish Aging Research Center.
References (459)
- et al.
Regulation of WRN helicase activity in human base excision repair
J. Biol. Chem.
(2004) - et al.
Mitochondrial base excision repair of uracil and AP sites takes place by single-nucleotide insertion and long-patch DNA synthesis
DNA Repair (Amst)
(2008) - et al.
A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification
DNA Repair (Amst)
(2007) - et al.
Centrosome protein centrin 2/caltractin 1 is part of the xeroderma pigmentosum group C complex that initiates global genome nucleotide excision repair
J. Biol. Chem.
(2001) - et al.
Initiating cellular stress responses
Cell
(2004) - et al.
Mitochondria, oxidants, and aging
Cell
(2005) Free radicals and aging
Trends Neurosci.
(2004)- et al.
WRN interacts physically and functionally with the recombination mediator protein RAD52
J. Biol. Chem.
(2003) - et al.
Structure and function of mammalian facilitative sugar transporters
J. Biol. Chem.
(1993) - et al.
The neurological phenotype of ataxia-telangiectasia: solving a persistent puzzle
DNA Repair (Amst)
(2008)
The Werner syndrome protein confers resistance to the DNA lesions N3-methyladenine and O6-methylguanine: implications for WRN function
DNA Repair (Amst)
Werner syndrome protein: biochemical properties and functional interactions
Exp. Gerontol.
Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance
Trends Biochem. Sci.
ALS: a disease of motor neurons and their nonneuronal neighbors
Neuron
The role of oxidative damage and stress in aging
Mech. Ageing Dev.
Aging and neuronal replacement
Ageing Res. Rev.
The oxidative DNA lesion 8,5′-(S)-cyclo-2′-deoxyadenosine is repaired by the nucleotide excision repair pathway and blocks gene expression in mammalian cells
J. Biol. Chem.
The case for 8,5′-cyclopurine-2′-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum
Neuroscience
Regulation of brain glucose transporters by glucose and oxygen deprivation
Metabolism
Beta-amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer's disease
Biochem. Biophys. Res. Commun.
Attenuation of DNA polymerase beta-dependent base excision repair and increased DMS-induced mutagenicity in aged mice
Mutat. Res.
XRCC1 and DNA strand break repair
DNA Repair (Amst)
Somatic mitochondrial DNA mutations in single neurons and glia
Neurobiol. Aging
The mitochondrial transcription factor A functions in mitochondrial base excision repair
DNA Repair (Amst)
Involvement of XRCC1 and DNA ligase III gene products in DNA base excision repair
J. Biol. Chem.
The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response
Cell
Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target
Clin. Oncol. (R. Coll. Radiol.)
Promotion of Dnl4-catalyzed DNA end-joining by the Rad50/Mre11/Xrs2 and Hdf1/Hdf2 complexes
Mol. Cell.
Linkage between Werner syndrome protein and the Mre11 complex via Nbs1
J. Biol. Chem.
Glutamate neurotoxicity and diseases of the nervous system
Neuron
Expression of senescence-associated beta-galactosidase in enlarged prostates from men with benign prostatic hyperplasia
Urology
Ataxia-telangiectasia, an evolving phenotype
DNA Repair (Amst)
Formation of trans-4-hydroxy-2-nonenal- and other enal-derived cyclic DNA adducts from omega-3 and omega-6 polyunsaturated fatty acids and their roles in DNA repair and human p53 gene mutation
Mutat. Res.
The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM and interacts with the DNA strand break repair proteins XRCC1 and XRCC4
DNA Repair (Amst)
Repair of DNA covalently linked to protein
Mol. Cell.
The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1
J. Biol. Chem.
Is DNA repair compromised in Alzheimer's disease?
Neurobiol. Aging
Mitochondrial DNA damage as a mechanism of cell loss in Alzheimer's disease
Lab. Invest.
Novel DNA mismatch-repair activity involving YB-1 in human mitochondria
DNA Repair (Amst)
The genetic and molecular basis of Fanconi anemia
Mutat. Res.
Cell type-specific hypersensitivity to oxidative damage in CSB and XPA mice
DNA Repair (Amst)
Molecular and biological roles of Ape1 protein in mammalian base excision repair
DNA Repair (Amst)
No disease in the brain of a 115-year-old woman
Neurobiol. Aging
Cockayne syndrome group B protein promotes mitochondrial DNA stability by supporting the DNA repair association with the mitochondrial membrane
FASEB J.
The neurodegenerative disease protein aprataxin resolves abortive DNA ligation intermediates
Nature
Mislocalization of XPF-ERCC1 nuclease contributes to reduced DNA repair in XP-F patients
PLoS Genet.
Ataxia-ocular motor apraxia: a syndrome mimicking ataxia-telangiectasia
Ann. Neurol.
DNA replication is required To elicit cellular responses to psoralen-induced DNA interstrand cross-links
Mol. Cell. Biol.
Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra
J. Neurochem.
Oxidants, antioxidants, and the degenerative diseases of aging
Proc. Natl. Acad. Sci. USA
Cited by (258)
Kaempferol: Paving the path for advanced treatments in aging-related diseases
2024, Experimental GerontologyInteraction between mitophagy, cadmium and zinc
2023, Journal of Trace Elements in Medicine and BiologyPathways to healing: Plants with therapeutic potential for neurodegenerative diseases
2023, IBRO Neuroscience ReportsInflammaging, cellular senescence, and cognitive aging after traumatic brain injury
2023, Neurobiology of DiseaseAging: Epigenetic modifications
2023, Progress in Molecular Biology and Translational Science