Role of nucleotide excision repair proteins in oxidative DNA damage repair: an updating

DNA repair is a crucial factor in maintaining a low steady-state level of oxidative DNA damage. Base excision repair (BER) has an important role in preventing the deleterious effects of oxidative DNA damage, but recent evidence points to the involvement of several repair pathways in this process. Oxidative damage may arise from endogenous and exogenous sources and may target nuclear and mitochondrial DNA as well as RNA and proteins. The importance of preventing mutations associated with oxidative damage is shown by a direct association between defects in BER (i.e. MYH DNA glycosylase) and colorectal cancer, but it is becoming increasingly evident that damage by highly reactive oxygen species plays also central roles in aging and neurodegeneration. Mutations in genes of the nucleotide excision repair (NER) pathway are associated with diseases, such as xeroderma pigmentosum and Cockayne syndrome, that involve increased skin cancer risk and/or developmental and neurological symptoms. In this review we will provide an updating of the current evidence on the involvement of NER factors in the control of oxidative DNA damage and will attempt to address the issue of whether this unexpected role may unlock the difficult puzzle of the pathogenesis of these syndromes.     

The role of DNA repair in brain related disease pathology

Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions which create bursts of oxidative damage. Brain cells have a particularly high basal level of metabolic activity and use distinct oxidative damage repair mechanisms to remove oxidative damage from DNA and dNTP pools. Accumulation of this damage in the background of a functional DNA repair response is associated with normal aging, but defective repair in brain cells can contribute to neurological dysfunction. Emerging research strongly associates three common neurodegenerative conditions, Alzheimer's, Parkinson's and stroke, with defects in the ability to repair chronic or acute oxidative damage in neurons. This review explores the current knowledge of the role of oxidative damage repair in preserving brain function and highlights the emerging models and methods being used to advance our knowledge of the pathology of neurodegenerative disease.     

DNA repair and neurological disease: From molecular understanding to the development of diagnostics and model organisms

In both replicating and non-replicating cells, the maintenance of genomic stability is of utmost importance. Dividing cells can repair DNA damage during cell division, tolerate the damage by employing potentially mutagenic DNA polymerases or die via apoptosis. However, the options for accurate DNA repair are more limited in non-replicating neuronal cells. If DNA damage is left unresolved, neuronal cells die causing neurodegenerative disorders. A number of pathogenic variants of DNA repair proteins have been linked to multiple neurological diseases. The current challenge is to harness our knowledge of fundamental properties of DNA repair to improve diagnosis, prognosis and treatment of such debilitating disorders. In this perspective, we will focus on recent efforts in identifying novel DNA repair biomarkers for the diagnosis of neurological disorders and their use in monitoring the patient response to therapy. These efforts are greatly facilitated by the development of model organisms such as zebrafish, which will also be summarised.     

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

Neuronal DNA repair remains one of the most exciting areas for investigation, particularly as a means to compare the DNA repair response in mitotic (cancer) vs. post-mitotic (neuronal) cells. In addition, the role of DNA repair in neuronal cell survival and response to aging and environmental insults is of particular interest. DNA damage caused by reactive oxygen species (ROS) such as generated by mitochondrial respiration includes altered bases, abasic sites, and single- and double-strand breaks which can be prevented by the DNA base excision repair (BER) pathway. Oxidative stress accumulates in the DNA of the human brain over time especially in the mitochondrial DNA (mtDNA) and is proposed to play a critical role in aging and in the pathogenesis of several neurological disorders including Parkinson's disease, ALS, and Alzheimer's diseases. Because DNA damage accumulates in the mtDNA more than nuclear DNA, there is increased interest in DNA repair pathways and the consequence of DNA damage in the mitochondria of neurons. The type of damage that is most likely to occur in neuronal cells is oxidative DNA damage which is primarily removed by the BER pathway. Following the notion that the bulk of neuronal DNA damage is acquired by oxidative DNA damage and ROS, the BER pathway is a likely area of focus for neuronal studies of DNA repair. BER variations in brain aging and pathology in various brain regions and tissues are presented. Therefore, the BER pathway is discussed in greater detail in this review than other repair pathways. Other repair pathways including direct reversal, nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination and non-homologous end joining are also discussed. Finally, there is a growing interest in the role that DNA repair pathways play in the clinical arena as they relate to the neurotoxicity and neuropathy associated with cancer treatments. Among the numerous side effects of cancer treatments, major clinical effects include neurocognitive dysfunction and peripheral neuropathy. These symptoms occur frequently and have not been effectively studied at the cellular or molecular level. Studies of DNA repair may help our understanding of how those cells that are not dividing could succumb to neurotoxicity with the clinical manifestations discussed in the following article.     

DNA repair mechanisms in dividing and non-dividing cells

DNA damage created by endogenous or exogenous genotoxic agents can exist in multiple forms, and if allowed to persist, can promote genome instability and directly lead to various human diseases, particularly cancer, neurological abnormalities, immunodeficiency and premature aging. To avoid such deleterious outcomes, cells have evolved an array of DNA repair pathways, which carry out what is typically a multiple-step process to resolve specific DNA lesions and maintain genome integrity. To fully appreciate the biological contributions of the different DNA repair systems, one must keep in mind the cellular context within which they operate. For example, the human body is composed of non-dividing and dividing cell types, including, in the brain, neurons and glial cells. We describe herein the molecular mechanisms of the different DNA repair pathways, and review their roles in non-dividing and dividing cells, with an eye toward how these pathways may regulate the development of neurological disease.     

Nucleotide excision repair deficient mouse models and neurological disease

Nucleotide excision repair (NER) is a highly conserved mechanism to remove helix-distorting DNA base damage. A major substrate for NER is DNA damage caused by environmental genotoxins, most notably ultraviolet radiation. Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy are three human diseases caused by inherited defects in NER. The symptoms and severity of these diseases vary dramatically, ranging from profound developmental delay to cancer predisposition and accelerated aging. All three syndromes include neurological disease, indicating an important role for NER in protecting against spontaneous DNA damage as well. To study the pathophysiology caused by DNA damage, numerous mouse models of NER-deficiency were generated by knocking-out genes required for NER or knocking-in disease-causing human mutations. This review explores the utility of these mouse models to study neurological disease caused by NER-deficiency.     

DNA损伤修复过程表观遗传学改变

多种化学、物理及生物因素可诱发细胞DNA损伤,损伤后DNA损伤位点被相关损伤感受器识别,激活相应的修复通路进行DNA修复。越来越多的证据表明DNA甲基化状态、蛋白翻译后修饰、染色质重塑、miRNA等修饰方式参与了DNA的损伤修复。文章通过不同损伤修复通路中这些修饰的特点,阐述表观遗传学改变在DNA损伤修复发展过程中的作用机制。     

Crosstalk between autophagy and DNA repair systems

Autophagy and DNA repair are two essential biological mechanisms that maintain cellular homeostasis. Impairment of these mechanisms was associated with several pathologies such as premature aging, neurodegenerative diseases, and cancer. Intrinsic or extrinsic stress stimuli (e.g., reactive oxygen species or ionizing radiation) cause DNA damage. As a biological stress response, autophagy is activated following insults that threaten DNA integrity. Hence, in collaboration with DNA damage repair and response mechanisms, autophagy contributes to the maintenance of genomic stability and integrity. Yet, connections and interactions between these two systems are not fully understood. In this review article, current status of the associations and crosstalk between autophagy and DNA repair systems is documented and discussed.     

The role of chromatin proteins in DNA damage recognition and repair Mini-review

The structure of chromatin is the major factor determining the rate and efficiency of DNA repair. Chromatin remodeling events such as rearrangement of nucleosomes and higher order chromatin structures are indispensable features of repair processes. During the last decade numerous chromatin proteins have been identified that preferentially bind to different types of DNA damage. The HMGB proteins, which preferentially interact with DNA intrastrand crosslinks induced by cisplatin, are the archetypal example of such proteins. Several hypothetical models have been proposed describing the role of such damage-binding chromatin proteins. The damage shielding model postulates that binding of chromatin proteins to damaged DNA might disturb damage recognition by repair factors and impair its removal. Alternatively, the damage-recognition/signaling model proposes that the binding of specific chromatin proteins to damaged DNA could serve as a hallmark to be recognized by repair proteins. Additionally, the binding of specific chromatin proteins to damaged DNA could induce chromatin remodeling at the damage site and indirectly affect its repair. This paper aims to critically review current experimental data in relation to such possible roles of chromatin proteins.     

Chromatin remodeling and the maintenance of genome integrity

DNA damage of any type is threatening for a cell. If lesions are left unrepaired, genomic instability can arise, faithful transmission of genetic information is greatly compromised eventually leading the cell to undergo apoptosis or carcinogenesis. In order to access/detect and repair these damages, repair factors must circumvent the natural repressive barrier of chromatin. This review will present recent progress showing the intricate link between chromatin, its remodeling and the DNA repair process. Several studies demonstrated that one of the first events following specific types of DNA damage is the phosphorylation of histone H2A. This mark or the damage itself are responsible for the association of chromatin-modifying complexes near damaged DNA. These complexes are able to change the chromatin structure around the wounded DNA in order to allow the repair machinery to gain access and repair the lesion. Chromatin modifiers include ATP-dependent remodelers such as SWI/SNF and Rad54 as well as histone acetyltransferases (HATs) like SAGA/NuA4-related complexes and p300/CBP, which have been shown to facilitate DNA accessibility and repair in different pathways leading to the maintenance of genome integrity.     

Why do Neurons Enter the Cell Cycle?

Increasing evidence indicates that postmitotic, terminally differentiated neurons activate the cell cycle before death. The purpose of this cell cycle activation, however, remains elusive. In proliferating cells, cell cycle machinery is a major contributor to the DNA damage response, which is comprised of growth arrest. In quiescent cells such as terminally differentiated neurons, cell cycle-associated events may also be part of the DNA damage response. A link between DNA damage and repair, cell cycle regulation and cell death is becoming increasingly recognized for cycling cells but remains elusive for quiescent cells. Neurons are particularly susceptible to oxidative stress due to the high rate of oxidative metabolism in the brain and the low level of antioxidant enzymes compared to other somatic tissues. This is supported by fact that the intracellular end point of many neurotoxic stimuli is oxidative stress, which also represents a major cause of the neuropathology underlying a variety of neurodegenerative diseases. DNA is perhaps the major target of oxyradicals. Thus, oxidative stress may cause DNA damage, which is countered by a complex defense mechanism, the DNA damage response, which involves not only the elimination of DNA damage, but its coordination with other cellular processes such as cell-cycle progression, together directing to preserve genomic integrity. The function of such response is the removal of DNA damage by DNA repair pathways, or the elimination of damaged cells via apoptosis. The present review discusses the idea that the cell cycle machinery is a critical element of the DNA damage response not only in cycling, but also quiescent cells, and may bear the same function: to repair the damage or initiate apoptosis if the damage is too extensive to be repaired.     

When repair meets chromatin: First in series on chromatin dynamics

In eukaryotic cells, the inheritance of both the DNA sequence and its organization into chromatin is critical to maintain genome stability. This maintenance is challenged by DNA damage. To fully understand how the cell can tolerate genotoxic stress, it is necessary to integrate knowledge of the nature of DNA damage, its detection and its repair within the chromatin environment of a eukaryotic nucleus. The multiplicity of the DNA damage and repair processes, as well as the complex nature of chromatin, have made this issue difficult to tackle. Recent progress in each of these areas enables us to address, both at a molecular and a cellular level, the importance of inter-relationships between them. In this review we revisit the ‘access, repair, restore’ model, which was proposed to explain how the conserved process of nucleotide excision repair operates within chromatin. Recent studies have identified factors potentially involved in this process and permit refinement of the basic model. Drawing on this model, the chromatin alterations likely to be required during other processes of DNA damage repair, particularly double-strand break repair, are discussed and recently identified candidates that might perform such alterations are highlighted.     

RNF8/RNF168信号通路在DNA损伤修复中的作用

细胞内DNA会受部分外界因素(如紫外辐射,电离辐射和化学毒素)和内部因素(如复制错误)的影响而发生损伤,包括DNA双链断裂、DNA错配和DNA交链等。DNA损伤发生后,损伤部位会被一些蛋白识别,进而招募一系列蛋白至损伤部位,形成一个修复系统。DNA双链断裂是最严重的一种DNA损伤,错误修复往往导致疾病的发生。DNA双链断裂(double strand break, DSB)后,细胞启动RNF8/RNF168信号通路进行修复。RNF8和RNF168是这条通路的枢纽蛋白;53BP和BRCA1是关键的效应蛋白,决定着DSB修复的方式;组蛋白泛素化、磷酸化和甲基化等翻译后修饰是这条通路顺利进行的基本条件;染色质重塑、泛素化酶/去泛素化酶平衡和蛋白稳定性是这条通路的主要调节方式。本综述对RNF8/RNF168信号通路进行了梳理总结,希望其能对相关研究者起到参考作用。     

Molecular mechanisms of DNA damage and repair: progress in plants

Despite stable genomes of all living organisms, they are subject to damage by chemical and physical agents in the environment (e.g., UV and ionizing. radiations, chemical mutagens, fungal and bacterial toxins, etc.) and by free radicals or alkylating agents endogenously generated in metabolism. DNA is also damaged because of errors during its replication. The DNA lesions produced by these damaging agents could be altered base, missing base, mismatch base, deletion or insertion, linked pyrimidines, strand breaks, intra- and inter-strand cross-links. These DNA lesions could be genotoxic or cytotoxic to the cell. Plants are most affected by the UV-B radiation of sunlight, which penetrates and damages their genome by inducing oxidative damage (pyrimidine hydrates) and cross-links (both DNA protein and DNA-DNA) that are responsible for retarding the growth and development. The DNA lesions can be removed by repair, replaced by recombination, or retained, leading to genome instability or mutations or carcinogenesis or cell death. Mostly organisms respond to genome damage by activating a DNA damage response pathway that regulates cell-cycle arrest, apoptosis, and DNA repair pathways. To prevent the harmful effect of DNA damage and maintain the genome integrity, all organisms have developed various strategies to either reverse, excise, or tolerate the persistence of DNA damage products by generating a network of DNA repair mechanisms. A variety of different DNA repair pathways have been reported that include direct reversal, base excision repair, nucleotide excision repair, photoreactivation, bypass, double-strand break repair pathway, and mismatch repair pathway. The direct reversal and photoreactivation require single protein, all the rest of the repair mechanisms utilize multiple proteins to remove or repair the lesions. The base excision repair pathway eliminates single damaged base, while nucleotide excision repair excises a patch of 25- to 32-nucleotide-long oligomer, including the damage. The double-strand break repair utilizes either homologous recombination or nonhomologous endjoining. In plant the latter pathway is more error prone than in other eukaryotes, which could be an important driving force in plant genome evolution. The Arabidopsis genome data indicated that the DNA repair is highly conserved between plants and mammals than within the animal kingdom, perhaps reflecting common factors such as DNA methylation. This review describes all the possible mechanisms of DNA damage and repair in general and an up to date progress in plants. In addition, various types of DNA damage products, free radical production, lipid peroxidation, role of ozone, dessication damage of plant seed, DNA integrity in pollen, and the role of DNA helicases in damage and repair and the repair genes in Arabidopsis genome are also covered in this review.     

Polymorphisms in DNA repair and environmental interactions

The repair of damage to DNA is critical to the survival of a cell. However, not all organisms nor all individuals express a similar response to challenges to their genetic material. Numerous polymorphisms in genes involved in DNA repair have been found in individuals with DNA repair-related disease as well as in the general population. Studies of these variants are critical in understanding the response of the cell to DNA damage. In some cases, these changes predispose the carrier to a greatly increased risk of cancer. In other cases, the effects are subtler and depend on interactions between the alleles of several genes, or with environmental factors. Consequently, the health effects of exposure to genotoxic or carcinogenic compounds or agents can depend on the variations in these genes. This review will highlight some of the effects that variants, found in many of the genes involved in human DNA repair pathways, have on the response to damage, and their role in susceptibility of the cell and organism to environmental genotoxins. This review will concentrate on the mismatch repair, nucleotide repair, base excision repair, strand break repair, and direct alkyl repair pathways.