Elsevier

Mitochondrion

Volume 16, May 2014, Pages 38-49
Mitochondrion

Review
A short review on the implications of base excision repair pathway for neurons: Relevance to neurodegenerative diseases

https://doi.org/10.1016/j.mito.2013.10.007Get rights and content

Highlights

  • Oxidative DNA damage repair in CNS

  • Preferential repair pathways employed by neurons

  • Nuclear vs. mitochondrial base excision repair-pathway choice for neurons

  • APE1/Ref-1 a multifunctional enzyme

  • New discoveries in the field of APE1/Ref-1

Abstract

Oxidative DNA damage results from the attack by reactive oxygen and nitrogen species (ROS/RNS) on human genome. This includes base modifications such as oxidized bases, abasic (AP) sites, and single-strand breaks (SSBs), all of which are repaired by the base excision repair (BER) pathway, one among the six known repair pathways. BER-pathway in mammalian cells involves several evolutionarily conserved proteins and is also linked to genome replication and transcription. The BER-pathway enzymes, namely, DNA glycosylases (DGs) and the end-processing proteins such as abasic endonuclease (APE1), form complexes with downstream repair enzymes via protein–protein and DNA–protein interactions. An emerging concept for BER proteins is their involvement in non-canonical functions associated to RNA metabolism, which is opening new interesting perspectives. Various mechanisms that are underlined in maintaining neuronal cell genome integrity are identified, but are inconclusive in providing protection against oxidative damage in neurodegenerative disorders, main emphasis is given towards the role played by the proteins of BER-pathway that is discussed. In addition, mechanisms of action of BER-pathway in nuclear vs. mitochondria as well as the non-canonical functions are discussed in connection to human neurodegenerative diseases.

Introduction

DNA damage is balanced with repair in a homeostatic process, and when damage exceeds the repair, final outcome may be cell cycle arrest, apoptosis or genome mutation. DNA damage occurs due to various external and internal causes. In neuronal cells, most of the DNA damage is repaired by the base excision repair (BER) pathway, as neuronal cells are partially differentiated cells and replication derived repair is not possible in these cells. It is very important to study the mechanisms and enzymes involved in BER-pathway for neuronal survival. In neuronal cells, the role of different proteins in BER-pathway in both nucleus and mitochondria is not fully elucidated, yet.

Section snippets

Roles of base excision repair in oxidative DNA damage repair

Mammalian cells are constantly exposed to stress from external and internal agents. Oxidative stress is a common feature of all stresses, and to maintain cellular integrity, mammalian cells have evolved different repair mechanisms. Various chemical events may lead to DNA damage including hydrolysis and exposure to reactive oxygen substances and other reactive metabolites (Bergamini et al., 2004). In normal dividing cells, the DNA damage is sensed through different cell cycle checkpoints, and if

Sources of endogenous and exogenous DNA damage to neuronal cells

Damage to DNA can be induced by several chemical reactive species and physical agents or may occur spontaneously through intrinsic instability of chemical bonds in DNA (Table 1). Even under normal physiologic conditions, DNA is continuously being damaged (Altieri et al., 2008). These attacks can be divided into two broad categories: exogenous and endogenous (Altieri et al., 2008). Exogenous and environmental sources of oxidation relate to specific exposures of the organism to ionizing

X-ray repair cross-complementing 1 (XRCC1) protein

XRCC1 protein binds to the DNA containing nicks or short gaps. It functions differently by acting as a scaffold protein for recruiting other partners. XRCC1 physically interacts with various BER proteins (Hegde et al., 2008). XRCC1 interacts with end cleansing enzymes like APE1, PNKP, and flap endonuclease 1 [FEN1] (Fortini and Dogliotti, 2007). It plays an important role in the activation of DNA Ligase IIIα and also physically interacts with it (Simsek et al., 2011). XRCC1 plays a central role

Flap endonuclease (FEN1)

FEN1 is a member of flap endonucleases and helps in processing of flap generated during BER activity (Klungland and Lindahl, 1997, Tsutakawa et al., 2011). This enzyme processes the 5′ single strand DNA or RNA called as 5′ flaps (Klungland and Lindahl, 1997). FEN1's efficiency is very critical for the human DNA replication and generates ~ 50 million Okazaki primers each cycle. The flap endonuclease family contains mainly FEN1, Exo1, and GEN1, all these are Mg2 +-dependent nucleases (Zharkov, 2008

Differences Between Nuclear vs. Mitochondrial BER-pathway in neuronal cells

The CNS comprises various types of cells including neurons and glial cells [astrocytes, oligodendrocytes and microglial cells] (Fawcett and Asher, 1999). In the brain, neurons are protected from extracellular genotoxic chemicals because of its blood–brain barrier (BBB), but internal sources are main causes of damage (Gesuete et al., 2011, Vries et al., 1997). Mitochondrial DNA repair is of greater importance, as many of the NDs are related with the mtDNA defects and mitochondrial repair defects

Single nucleotide polymorphisms (SNPs) in BER enzymes in neurodegenerative diseases (NDs)

NDs, like AD, PD and HD, are complex multifactorial NDs (Sheikh et al., 2013). In general there are various causes for the development of these neurodegenerative diseases. Here, we have listed the association between common polymorphisms of BER genes and the development of ND. Commonly studied genes for single nucleotide substitutions that are encoding for OGG1, APEX1, XRCC1 and PARP-1 are summarized in Table 3.

Relevance of non-canonical functions of BER proteins for neuronal cell damage

Increasing evidences highlight the paradigm that several DNA repair enzymes of BER-pathway may exert non-canonical functions that differ from the “orthodox” activity in maintenance of genome stability (Antoniali et al., 2013). This is an emerging paradigm observed for many proteins belonging to DNA repair pathways. Among these enzymes, for example, many recent works have reported the relevance and involvement of PARP proteins and APE1 in multiple steps of gene regulation and RNA metabolism.

BER in RNA

Due to its intrinsic physico-chemical properties (i.e. mostly single-stranded and with bases not protected by hydrogen bonding or binding to specific proteins) and to its relative higher amount, RNA results to be more susceptible to oxidative insults than DNA (Moreira et al., 2008). Not only 8-hydroxyguanine (8-OHG) but also 5-hydroxycytidine, 5-hydroxyuridine and 8-hydroxyadenosine have been identified in oxidized RNA (Yanagawa et al., 1992). While oxidative damage to DNA is essentially

Conclusions and future perspectives

Oxidative genome damage and repair that include base lesions, AP sites and their oxidation products via BER-pathway both in the nucleus and mitochondria are critical for maintaining genome integrity and neuronal survival where the endogenous ROS/RNS levels are high due to high consumption of glucose and other metabolic activities. The importance of BER-pathway in prevention of NDs was initially questioned by the lack of linkage between accumulation of oxidized bases, AP sites and SSBs and human

Acknowledgments

A.K.M is supported by Alzheimer's Association, USA, NIRG-11-203527 grant. G.T. is supported by the Regione Friulia Venezia Giulia for the Project 'MINA' under the program entitled: "Programma per la Cooperazione Transfrontaliera Italia-Slovenia 2007–2013". B.S. thankfully acknowledges institutional fellowship from the Central University of Punjab, Bathinda (CUPB). Dr. Monisha Dhiman, Centre for Genetic Diseases and Molecular Medicine, School of Emerging Life Science Technologies, Central

References (169)

  • J. Fawcett et al.

    The glial scar and central nervous system repair

    Brain Res. Bull.

    (1999)
  • M.L. Fishel et al.

    DNA repair in neurons: so if they don't divide what's to repair?

    Mutat. Res.

    (2007)
  • P. Fortini et al.

    Base damage and single-strand break repair: mechanisms and functional significance of short-and long-patch repair subpathways

    DNA Repair

    (2007)
  • J.C. Fromme et al.

    DNA glycosylase recognition and catalysis

    Curr. Opin. Struct. Biol.

    (2004)
  • H. Fung et al.

    A vital role for Ape1/Ref1 protein in repairing spontaneous DNA damage in human cells

    Mol. Cell

    (2005)
  • S. Gajewski et al.

    Analysis of the active-site mechanism of tyrosyl-DNA phosphodiesterase I: a member of the phospholipase D superfamily

    J. Mol. Biol.

    (2012)
  • H. Gray et al.

    Purification and identification of subunit structure of the human mitochondrial DNA polymerase

    J. Biol. Chem.

    (1992)
  • T.K. Hazra et al.

    Purification and characterization of NEIL1 and NEIL2, members of a distinct family of mammalian DNA glycosylases for repair of oxidized bases

  • M.L. Hegde et al.

    Specific inhibition of NEIL-initiated repair of oxidized base damage in human genome by copper and iron: potential etiological linkage to neurodegenerative diseases

    J. Biol. Chem.

    (2010)
  • M.L. Hegde et al.

    Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases

    Mech. Ageing Dev.

    (2012)
  • J.H. Houtgraaf et al.

    A concise review of DNA damage checkpoints and repair in mammalian cells

    Cardiovasc. Revasc. Med.

    (2006)
  • H. Interthal et al.

    Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages

    J. Biol. Chem.

    (2005)
  • Y. Jiang et al.

    Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress: use of APE1 small molecule inhibitors to delineate APE1 functions

    DNA Repair

    (2009)
  • B.-G. Ju et al.

    Activating the PARP-1 sensor component of the Groucho/TLE1 corepressor complex mediates a CaMKinase IIδ-dependent neurogenic gene activation pathway

    Cell

    (2004)
  • M.Y. Kim et al.

    NAD+-dependent modulation of chromatin structure and transcription by nucleosome binding properties of PARP-1

    Cell

    (2004)
  • G.E. Kisby et al.

    DNA repair modulates the vulnerability of the developing brain to alkylating agents

    DNA Repair

    (2009)
  • I.I. Kruman et al.

    Suppression of uracil-DNA glycosylase induces neuronal apoptosis

    J. Biol. Chem.

    (2004)
  • M. Li et al.

    Identification and characterization of mitochondrial targeting sequence of human apurinic/apyrimidinic endonuclease 1

    J. Biol. Chem.

    (2010)
  • M. Li et al.

    Human AP endonuclease/redox factor APE1/ref-1 modulates mitochondrial function after oxidative stress by regulating the transcriptional activity of NRF1

    Free Radic. Biol. Med.

    (2012)
  • Y. Liu et al.

    DNA polymerase β and flap endonuclease 1 enzymatic specificities sustain DNA synthesis for long patch base excision repair

    J. Biol. Chem.

    (2005)
  • Y. Liu et al.

    Coordination between polymerase β and FEN1 can modulate CAG repeat expansion

    J. Biol. Chem.

    (2009)
  • S. Mandal et al.

    Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3′-phosphatase in maintenance of mitochondrial genome

    J. Biol. Chem.

    (2012)
  • C. Marietta et al.

    Expression of long-patch and short-patch DNA mismatch repair proteins in the embryonic and adult mammalian brain

    Mol. Brain Res.

    (1998)
  • P.A. Aas et al.

    Human and bacterial oxidative demethylases repair alkylation damage in both RNA and DNA

    Nature

    (2003)
  • A. Adamczyk et al.

    Alzheimer's disease related peptides affected cholinergic receptor mediated poly (ADP-ribose) polymerase activity in the hippocampus

    Folia Neuropathol.

    (2005)
  • F. Altieri et al.

    DNA damage and repair: from molecular mechanisms to health implications. Antioxid

    Redox Signal

    (2008)
  • J.C. Ame et al.

    The PARP superfamily

    Bioessays

    (2004)
  • G. Antoniali et al.

    Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example

    Antioxid. Redox Signal.

    (2013)
  • Y. Ariumi et al.

    DNA damage sensors ATM, ATR, DNA-PKcs, and PARP-1 are dispensable for human immunodeficiency virus type 1 integration

    J. Virol.

    (2005)
  • T. Barnes et al.

    Identification of apurinic/apyrimidinic endonuclease 1 (APE1) as the endoribonuclease that cleaves c-Myc mRNA

    Nucleic Acids Res.

    (2009)
  • C.M. Bergamini et al.

    Oxygen, reactive oxygen species and tissue damage

    Curr. Pharm. Des.

    (2004)
  • K.K. Bhakat et al.

    Transcriptional regulatory functions of mammalian AP-endonuclease (APE1/Ref-1), an essential multifunctional protein

    Antioxid. Redox Signal.

    (2009)
  • D. Branzei et al.

    Regulation of DNA repair throughout the cell cycle

    Nat. Rev. Mol. Cell Biol.

    (2008)
  • R. Brem et al.

    XRCC1 is required for DNA single-strand break repair in human cells

    Nucleic Acids Res.

    (2005)
  • G.C. Brown

    Control of respiration and ATP synthesis in mammalian mitochondria and cells

    Biochem. J.

    (1992)
  • J.A. Calvo et al.

    Aag DNA glycosylase promotes alkylation-induced tissue damage mediated by Parp1

    PLoS Genet.

    (2013)
  • R. Chattopadhyay et al.

    Identification and characterization of mitochondrial abasic (AP)-endonuclease in mammalian cells

    Nucleic Acids Res.

    (2006)
  • D. Chen et al.

    Detection of DNA base-excision repair activity for oxidative lesions in adult rat brain mitochondria

    J. Neurosci. Res.

    (2000)
  • A. Copani et al.

    DNA polymerase-beta is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid

    J. Neurosci.

    (2006)
  • I. Cymerman et al.

    EXOG, a novel paralog of endonuclease G in higher eukaryotes

    Nucleic Acids Res.

    (2008)
  • Cited by (44)

    • Tea polyphenols improve the memory in aging ovariectomized rats by regulating brain glucose metabolism in vivo and in vitro

      2021, Journal of Functional Foods
      Citation Excerpt :

      The integrity of mitochondria is a necessary condition for its normal function (Jonsson et al., 2012). The level of energy metabolism in the brain is significantly reduced before clinical symptoms appear in AD patients (Mantha et al., 2014), and energy metabolism disorder is also becoming increasingly significant with the increasing cognitive impairment because the damage of mitochondrial structure and function (Islam, 2017). The main source of brain energy is glucose.

    • Transcription coupled base excision repair in mammalian cells: So little is known and so much to uncover

      2021, DNA Repair
      Citation Excerpt :

      Relatively high level of ROS is generated in the brain because of its high metabolic activity. ROS-induced oxidative damage and its repair deficiency have been linked to the generation of neurodegenerative disorders [10,12,13,147–151]. Because the neurons do not replicate, the levels of replication and associated repair proteins in the brain are low; hence, short patch BER/SSBR appears to be the predominant mode of repair [152].

    • DNA Repair Protein APE1 Degrades Dysfunctional Abasic mRNA in Mitochondria Affecting Oxidative Phosphorylation

      2021, Journal of Molecular Biology
      Citation Excerpt :

      Loss of APE1 expression determines a plethora of effects, among which are mitochondrial membrane depolarization and induction of mitochondrial-mediated apoptosis.34 One of the results of mitochondrial stress is the increase of mtDNA content to limit the possible detrimental effects of ROS on DNA and, as a consequence, on the mitochondrial protein synthesis.35 To prove that silencing of APE1 is a stress-causing condition for mitochondria in our cell model, we measured the mtDNA content before and after APE1 knockdown in HeLa cells.

    • The effect of the use of copper carbonate and copper nanoparticles in the diet of rats on the level of β-amyloid and acetylcholinesterase in selected organs

      2021, Journal of Trace Elements in Medicine and Biology
      Citation Excerpt :

      APE-1 is also responsible for repairing oxidative damage, maintaining cellular redox homeostasis, cell proliferation, modification of the cytoskeleton, and cellular energy metabolism [82,84,85]. According to Mantha et al. [86,87] and Smith et al. [88], neurotoxic reactions induced by the formation of βAP stimulate the function of the key enzyme APE-1, as do unphosphorylated tau protein and excessive Ca2+ influx into the cell. The analysis of the effect of the use of copper carbonate and copper nanoparticles in the diet of rats on the level of β-amyloid and acetylcholinesterase in selected organs showed that the use of CuNPs in the diet of rats increases the level of β-amyloid in the brain tissue and the level of AChE to a similar extent as the use of copper in the form of CuCO3.

    View all citing articles on Scopus
    View full text