ReviewA short review on the implications of base excision repair pathway for neurons: Relevance to 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
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