DNA-PK and P38 MAPK: A Kinase Collusion in Alzheimer’s Disease?
Division of Neurotoxicology, National Center for Toxicological Research, US Food and Drug Administration, USA
- *Corresponding Author:
- Jyotshna Kanungo PhD
Division of Neurotoxicology,
National Center for Toxicological Research
U.S. Food and Drug Administration,
3900 NCTR Road, Jefferson, AR 72079, USA
E-mail: [email protected]
Received Date: April 07, 2017; Accepted Date: April 14, 2017; Published Date: April 19, 2017
Citation: Kanungo J (2017) DNA-PK and P38 MAPK: A Kinase Collusion in
Alzheimer’s Disease? Brain Disord Ther 6:230. doi: 10.4172/2168-975X.1000230
Copyright: © 2017 Kanungo J. This is an open-access article distributed under
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use, distribution, and reproduction in any medium, provided the original author and
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The pathogenesis of Alzheimer’s disease (AD), characterized by prevalent neuronal death and extracellular deposit of amyloid plaques, is poorly understood. DNA lesions downstream of reduced DNA repair ability have been reported in AD brains. Neurons predominantly use a mechanism to repair double-strand DNA breaks (DSB), which is non-homologous end joining (NHEJ). NHEJ requires DNA-dependent protein kinase (DNA-PK) activity. DNA-PK is a holoenzyme comprising the p460 kD catalytic subunit (DNA-PKcs) and its activator Ku, a heterodimer of p86 and p70 subunits. Ku first binds and then recruits DNA-PKcs to double-stranded DNA ends before NHEJ process begins. Studies have shown reduced NHEJ activity as well as DNA-PKcs and Ku protein levels in AD brains suggesting possible contribution of unrepaired DSB to AD development. However, normal aging brains also show reduced DNA-PKcs and Ku levels thus challenging the notion of any direct link between NHEJ and AD. Another kinase, p38 MAPK is induced by various DNA damaging agents and DSB itself. Increased DNA damage with aging could induce p38 MAPK and its induction may be sustained when DNA repair is compromised in the brain with reduced DNA-PK activity. Combined, these two events may potentially set the stage for an awry nervous system approaching AD.
Ku; DNA repair; NHEJ; ROS; Amyloid beta
AD: Alzheimer’s Disease; ATM: Ataxia Telangiectasia Mutated Protein; ATR: Ataxia Telangiectasia and Rad3- related Protein; BER: Base Excision Repair; Cdk5: Cyclin Dependent Kinase 5; DNA-PK: DNA-Dependent Protein Kinase; DSB: Double Strand Breaks; DSBR: Double Strand Break Repair; HR: Homologous Recombination; MAPK: Mitogen Activated Protein Kinase; ERK: Extracellular Signal-Regulated Kinase; MKK6: Mitogen-activated Protein Kinase Kinase 6; NER: Nucleotide Excision Repair; Lig IV: Ligase IV; NHEJ: Non Homologous End Joining; NFT: Neurofibrillary Tangle; rRNA: Ribosomal RNA; SSBR: Single Strand Break Repair; XLF: XRCC4 Like Factor; XRCC4: X-ray Repair Cross Complementing Protein 4.
Alzheimer’s disease (AD) is a neurodegenerative disease affecting ~24 million people worldwide and this number could double by 2030 . AD is characterized by specific neuronal death with accumulated neurofibrillary tangles (NFT) and extracellular amyloid beta (Aβ) deposits . These characteristics are accompanied by memory impairment, cognitive decline and synaptic dysfunction . Aβ which is produced by serial cleavage of the amyloid precursor protein (APP), directly injures neurons of the neocortical and limbic system . By indirectly activating the microglia that release pro-inflammatory cytokines and reactive oxygen species (ROS), Aβ exerts additional neurotoxic effects [5,6]. Other contributors to AD pathogenesis include apolipoprotein E genotype ; neurofilament and Tau hyperphosphorylation [8-11], and Aβ generation . AD being a multifactorial disease , no single factor has been identified as the main contributor to its development [14-17]. In various studies, oxidative stress has been linked to AD pathogenesis [18-20]. Oxidative stress can cause DNA damage, alter the levels and activity of DNArepair proteins [21,13]. Thus, oxidative stress can induce cellular damage by ROS generation, and elevated levels of oxidative damage in DNA are observed in AD brains . Cellular DNA damage and repair follow a homeostatic process, but as the cells age, the damage exceeds repair consequently disrupting the homeostasis [23,24]. Aging, a major risk factor in AD, is associated with cumulative oxidative stress and it is proposed that elevated levels of oxidized nucleic acids in neurons can lead to neuronal dysfunction in AD patients [25-27] thus linking oxidative damage to neurodegeneration . Accumulation of DNA damage due to dysfunctional DNA repair machinery can create events contributing to AD [29-32]. Furthermore, studies show that some human hereditary genetic defects in the DNA repair system are apparent during early onset and progressive neurodegeneration [33,34]. Understanding the factors responsible for DNA repair defects can unravel potential intervention points of AD pathogenesis caused by genome instability.
DNA repair, DNA-PK and Aβ
DNA damage induces the expression and activity of many kinases including the members of the PI-3 kinase family . One of these kinases, the DNA-dependent protein kinase (DNA-PK) preferentially phosphorylates the serines (S) and threonines (T) of its target substrates . DNA-PK is a holoenzyme comprising a catalytic subunit (DNAPK cs) of p460 and a regulatory subunit (Ku) of 70 kD (Ku70) and 80 kD (Ku80) heterodimer. Ku possesses the ability to bind to DNA ends [37,38]. DNA-PK plays a role in transcription, DNA recombination, and DNA repair [39-42]. When not associated with DNA-PKcs, Ku independently binds DNA ends in a sequence-independent manner . However, Ku is essential for targeting DNA-PKcs to the damaged DNA sites in living cells . Studies show that double strand DNA breaks (DSB) can activate DNA-PK activity both in trans (via kinase autophosphrylation) or cis (via specific DNA strand orientation and base sequence) modes [45-47].
DNA repair pathways used by cells include base excision repair (BER), nucleotide excision repair (NER), single strand break repair (SSBR), and double strand break repair (DSBR). Double strand break (DSB) being the most lethal, in eukaryotes, two major DSB repair pathways operate; non-homologous end joining (NHEJ) and homologous recombination (HR). In higher order organisms, NHEJ functions as the predominant pathway for DSBR throughout the cell cycle [48-50], whereas HR functions are limited to the S and G2 stages of the cell cycle . Specifically, DNA-PK actively engages in accessing the DNA ends during NHEJ [52,53].
NHEJ is the predominant dsDNA repair pathway in mammalian cells  and is more error-prone compared to HR as it acts at the DNA break points and the ensuing repair process can result in a loss of one or a few nucleotides. Fortunately, most of the higher eukaryote genome is non-coding. Therefore, errors resulting from DSB repair by NHEJ rarely lead to detriments. Nonetheless, with aging, these non-detrimental errors eventually can cause genome instability upon progressive accumulation, and cause cell death or dysfunction. It is important to note that 10% of p53 mutations in human cancers reportedly occurred due to deletions resulting from compromised NHEJ . Mature postmitotic neurons do not undergo proliferation [56,57], but they are one of the most metabolically and transcriptionally active cells . Due to this reason, these neurons can be more vulnerable to DNA damageinduced injury. In post-mitotic neurons, since NHEJ is the predominant pathway for DSB repair [59,60], mice deficient in DSB repair pathway components (DNA Ligase IV, XRCC4, Ku70 and Ku 80) (Figure 1) show robust apoptosis of these neurons [12,61]. Furthermore, mice with defective NHEJ undergo accelerated aging. Severity of the loss of NHEJ activity in the developing brain manifests in prenatal lethality and adult neurodegenerative diseases [12,62,63].
Figure 1: Schematic presentation of a potential link of DNA double strand breaks (DSB), DNA-PK and p38α MAPK in normal and AD brains. Upon induction of DSBs either by normal aging/ROS or other DNA damaging agents, Ku80/Ku70 andDNA-PKcs and are rapidly recruited to DNA ends, and DNA repair occurs as it would in normal brains. However, in AD brains, in addition to formation of Aβ oligomers from Aβ peptides, sustained DSBs in the genome would cause genome instability leading to the loss of normal neuronal activity. Additionally, with depleted DNA-PK activity andNHEJ, sustained DSBs could activate p38α MAPK via ATM triggering neuronal death, potentially mediated by one of the downstream pathways being ERK MAPK down regulation and another via c-jun activation. Disruption of somatostatin signaling via Ku80 (a somatostatin receptor) depletion may also lead to Aβ oligomerization, a prime trigger of AD. Shaded areas show normal (gray) and deregulated sequences of events (purple).
Post-mitotic neurons that are terminally differentiated, when triggered to re-enter cell cycle following chronic or acute insults inducing DNA damage and/or oxidative stress, undergo apoptosis [64,65]. Neurons re-entering cell cycle are prone to accrue DNA damage [65,66]. Therefore, it is possible that DNA replication is a consequence of cell cycle re-entry that precedes neurodegeneration in AD brains . In addition, reactive oxygen/nitrogen species can cause misdirected and inefficient DNA replication, called ‘replication stress’ [68,69], which during AD pathogenesis can lead to genomic instability thus facilitating Aβ accumulation and deregulation of cell cycles. In post-mitotic neurons, these adverse events can be further amplified with the existence of defective DNA repair systems leading to accumulation of additional DNA damages and genomic instabilities [70,71]. It is plausible that intracellular increase in DNA content reported in AD brains [72,67] could originate from these dual events. In fact, it has been reported that DNA-PKcs mutant cells under stress undergo non-arrested replication . Also suggested is a possibility that accumulated single-stranded DNA (ssDNA) at replication forks may create aberrant DNA structures leading to DSBs that activate DNAPK . Based on these findings, it is apparent that neurons deficient in DNA-PK activity could sustain unhindered replication stress leading to genome instability (Figure 1). In physiologic conditions, one of the most important roles DNA-PK plays is sensing the DNA damage  and then, inducing signaling pathways that can lead to programmed cell death . In Ku80-/- mice, defective NHEJ and telomere maintenance with premature aging have been reported [77,78]. Reductions in Ku80 and DNA-PKcs protein levels as well as Ku80’s DNA-binding ability following severe ischemic injury leading to neuronal death in rabbits have also been shown . Furthermore, although not significantly different from the age-matched controls, reduced Ku-DNA binding in extracts of post-mortem AD mid-frontal cortex suggests a potential link to reduced levels of Ku and DNA-PKcs proteins . Reduced DNA-PKcs expression in neurons and astrocytes of AD brains as well as in age-matched controls has been reported . Compared to normal subjects, reduced NHEJ activity in the cortical extracts of AD brains and significantly lower levels of DNA-PKcs in the AD brain extracts have also been reported  suggesting a critical role of DNA-PK-mediated NHEJ in brain health.
Other than its essential role in NHEJ, since DNA-PK is also a critical player in cell survival/death and gene transcription, it is compelling to directly link reduced levels of DNA-PK and Ku with less proficient NHEJ to neurodegeneration occurring in AD brains. Already challenged with this condition, additional DNA damage caused by agents such as ROS (Figure 1) to the neurons may misdirect them to re-enter cell cycle albeit unsuccessfully, which in turn can lead to accumulation of excessive genomic damage causing neuronal death. Therefore, it’s most likely that reduced levels of DNA-PKcs and Ku80/Ku70 create the detrimental upstream event before the advent of AD .
The mechanism of how reduced DNA-PK activity may be linked to Aβ is best shown in in vitro studies. For example, in NGF-differentiated PC12 cells, sub-lethal levels of aggregated Aβ 25-35 inhibited DNAPK activity as did hydrogen peroxide . It is likely that Aβ -induced ROS-mediated DNA-PKcs degradation via carbonylation, an irreversible oxidative protein modification [85,86]. Conversely, cultured hippocampal neurons from severe combined immunodeficient (SCID) mice that lack DNA-PK activity have been shown to be hypersensitive to apoptosis upon exposure to Aβ . In a normal individual however, whether Aβ induced attenuation of DNA-PK activity compromising NHEJ is linked to the onset of AD awaits examination.
P38 MAPK and Aβ
The mitogen-activated protein kinase (MAPK) family of serine/ threonine kinases are activated by extracellular stimuli, such as growth factors, cytokines, hormones and cellular stresses and thus regulate a number of major cellular processes including cell growth, differentiation and survival . One of the major MAPK family members is, p38 MAPK . P38 MAPK activation can have both beneficial and adverse effects on cell growth and survival depending on the cell type and p38 MAPK subtype; for example, activated p38 MAPK pathway has an antiapoptotic effect during neuronal differentiation, but is pro-apoptotic in mature neurons exposed to various stresses such as excitotoxic stimuli [90,91]. Various DNA damaging agents including UV irradiation and ionizing radiation can induce p38 MAPK activity [92,93]. Activation of p38 MAPK by DSB-inducing agents occurs via phosphorylation of p38 MAPK itself .
Significantly higher level of activated p38 MAPK along with the activation of its upstream activator, mitogen-activated protein kinase kinase 6 (MKK6), have been reported in early stages of AD [95,96]. In the amyloid precursor protein (APP)-transgenic mice Aβ accumulation with increased p38 MAPK activity has been reported [97-99]. Aβ induces p38 MAPK activity (Figure 1) through activation of pro-inflammatory cytokines [100-102]. Inhibition of p38 MAPK activity suppressed expression of pro-inflammatory cytokines and consequently attenuated synaptic dysfunction causing behavioral alterations in an AD mouse model . Knocking down p38α MAPK in neurons from APP/presenilin 1(PS1) double transgenic mice that overexpress human mutated APP and PS1 enhanced autophagy and promoted BACE1 (β-site APP-cleaving enzyme) degradation resulting in reduced Aβ generation .
Activated-p38 MAPK has been shown to co-localize with cyclindependent kinase 5 (Cdk5) in Tg2576 mice, a murine model of AD . Cdk5 inhibition has been shown to be more neuroprotective compared to p38 MAPK/c-jun inhibition, which suggests that Cdk5 may act upstream regulating neurodegenerative pathways triggered by p38 MAPK . Deregulated Cdk5 triggers ROS generation , and ROS is known to activate p38 MAPK (Figure 1) [90,106,107]. Activated p38 MAPK upregulates its direct downstream target, c-Jun, a pro-apoptotic transcription factor that can potentially cause neuro-apoptosis in AD . Studies have shown that c-Jun expression is up-regulated in AD . Furthermore, c-Jun not only induces abnormal Aβ generation in AD via activation of the β-APP gene  but also promotes apoptosis in hippocampal neurons treated with Aβ [109,110]. Not surprisingly, neurons of c-Jun-null mice are resistant to Aβ -mediated toxicity . Thus, activation of p38 MAPK, either by DSB or Aβ or both (Figure1), can potentially injure the neurons by inducing further Aβ generation and activating its target c-jun, a pro-apoptotic transcription factor.
Activated p38 MAPK has been reported during early onset of AD . Up-regulation of p38 MAPK also occurs during microglial inflammation . Activated p38 MAPK localized to the NFT and the dystrophic neurites in AD brain . However, a direct link between p38 MAPK activation and NFT formation was ruled out indicating that p38 MAPK activation could cause neurodegeneration independent of NFT formation . Moreover, since activated p38 MAPK was present at a higher level in some early AD cases, but was noticed at a modest level in a few severe AD cases, it has been suggested that early activation of p38 MAPK may be critical at early stages of AD . In vitro studies have suggested that p38 MAPK dysregulation causes tau hyper-phosphorylation and formation of NFT in AD [115,116]. There is evidence that AD patients might benefit from p38 MAPK inhibitors . Although p38α and p38β inhibition has been shown to improve Aβ-induced long-term potentiation deficits [117,118], it also increases hyperexcitability in the APP transgenic mice . Therefore, the specific effects of p38 inhibitors remain unclear [119,120]. Furthermore, roles of other p38 kinases, p38γ and p38δ, in AD are not known. Recently, a beneficial role of p38γ in AD was reported in mice showing T205 phosphorylation of tau by p38γ to be partly responsible for inhibiting Aβ toxicity . In this context, determining threshold levels of specific activated p38 MAPK that can switch from a beneficial role in neuronal differentiation and development  to trigger adverse effects on the neuron may hold the key to understanding its contribution to AD.
Alteration in brain pathology in AD occurs many years prior to the manifestation of clinical cognitive decline . AD is a multifactorial disease and several factors contribute to its development. Identifying these factors or multiple pathways that go awry poses formidable challenges, as do attempts to link the specificity of these abnormalities to functional outcomes in the patients. For example, compared to other players associated with NHEJ, all three components of the DNAPK complex (DNA-PKcs, Ku80 and Ku70) are abundantly expressed in human cells  and how a reduction in any of the DNA-PK components in the brain that is also observed even in normally aging individuals [82,80] compromises NHEJ so as to contribute to AD development is intriguing. Given the complexity of AD, it is imperative to take into consideration additional factors such as p38 MAPK activation that could accentuate the effects of DNA-PK deficiency in an otherwise normally aging individual. Ku80 is also a specific somatostatin receptor  and can regulate DNA-PK activity through somatostatin signaling pathway . It has been speculated that Ku80 deficiency, therefore, can disrupt somatostatin signaling leading to Aβ generation (Figure 1) . During normal aging, since DNA-PK components are reduced, unrepaired DSBs could occur albeit at a level not sufficient to induce sustained p38 MAPK activation. In contrast, in AD cases, a threshold level of DSBs could induce p38 MAPK activation subsequently amplifying Aβ generation. Understanding the subtlety of the occurrences of these events would justify a deficiency of NHEJ during aging to be normal whereas NHEJ deficiency along with p38 MAPK activation to be pathogenic. Early prediction of AD might depend on capturing the timing of the onset of multiple pathway defects, such as DNA-PK, p38 MAPK and somatostatin signaling. This would not only help discern between normal aging-related events and triggers of AD but also enable identifying potential intervention points.
- Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, et al. (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9: 63-75 e62.
- Smith MA, Perry G (1997) The pathogenesis of Alzheimer disease: an alternative to the amyloid hypothesis. J Neuropathol Exp Neurol 56: 217.
- McKhann GM (2011) Changing concepts of Alzheimer disease. JAMA 305: 2458-2459.
- Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2: a006338.
- Czirr E, Wyss-Coray T (2012) The immunology of neurodegeneration. J Clin Invest 122: 1156-1163.
- Wyss-Coray T, Rogers J (2012) Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med 2: a006346.
- Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261: 921-923.
- Trojanowski JQ, Schmidt ML, Shin RW, Bramblett GT, Rao D, et al. (1993) Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol 3: 45-54.
- Selkoe DJ (1997) Alzheimer's disease: genotypes, phenotypes, and treatments. Science 275: 630-631.
- Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, et al. (2016) Alzheimer's disease. Lancet.
- Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, et al. (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68: 19-31
- Brooks PJ (2002) DNA repair in neural cells: basic science and clinical implications. Mutat Res 509: 93-108.
- Bucholtz N, Demuth I (2013) DNA-repair in mild cognitive impairment and Alzheimer's disease. DNA Repair (Amst) 12: 811-816.
- Barnes J, Dickerson BC, Frost C, Jiskoot LC, Wolk D, et al. (2015) Alzheimer's disease first symptoms are age dependent: Evidence from the NACC dataset. Alzheimers Dement 11: 1349-1357.
- Crutch SJ, Schott JM, Rabinovici GD, Boeve BF, Cappa SF, et al. (2013) Shining a light on posterior cortical atrophy. Alzheimers Dement 9: 463-465.
- Murray IV, Proza JF, Sohrabji F, Lawler JM (2011) Vascular and metabolic dysfunction in Alzheimer's disease: a review. Exp Biol Med (Maywood) 236: 772-782.
- van der Flier WM, Pijnenburg YA, Fox NC, Scheltens P (2011) Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE varepsilon4 allele. Lancet Neurol 10: 280-288.
- Aldred S, Bennett S, Mecocci P (2010) Increased low-density lipoprotein oxidation, but not total plasma protein oxidation, in Alzheimer's disease. Clin Biochem 43: 267-271.
- Bennett S, Grant MM, Aldred S (2009) Oxidative stress in vascular dementia and Alzheimer's disease: a common pathology. J Alzheimers Dis 17 : 245-257.
- Bennett G, Papamichos-Chronakis M, Peterson CL (2013) DNA repair choice defines a common pathway for recruitment of chromatin regulators. Nat Commun 4: 2084.
- Kanungo J (2016) DNA-PK Deficiency in Alzheimer's Disease. J Neurol Neuromedicine 1: 17-22.
- Wang J, Xiong S, Xie C, Markesbery WR, Lovell MA (2005) Increased oxidative damage in nuclear and mitochondrial DNA in Alzheimer's disease. J Neurochem 93: 953-962.
- Campisi J (2013) Aging, cellular senescence, and cancer. Annu Rev Physiol 75: 685-705.
- Rasmussen LJ, Shiloh Y, Bergersen LH, Sander M, Bohr VA, et al. (2013) DNA damage response, bioenergetics, and neurological disease: the challenge of maintaining brain health in an aging human population. Mech Ageing Dev 134: 427-433.
- Candore G, Bulati M, Caruso C, Castiglia L, Colonna-Romano G, et al. (2010) Inflammation, cytokines, immune response, apolipoprotein E, cholesterol, and oxidative stress in Alzheimer disease: therapeutic implications. Rejuvenation Res 13: 301-313.
- Lovell MA, Markesbery WR (2007) Oxidative damage in mild cognitive impairment and early Alzheimer's disease. J Neurosci Res 85: 3036-3040.
- Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21: 172-188.
- Hegde ML, Mantha AK, Hazra TK, Bhakat KK, Mitra S, et al.(2012) Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases. Mech Ageing Dev 133: 157-168.
- Lovell MA, Soman S, Bradley MA (2011) Oxidatively modified nucleic acids in preclinical Alzheimer's disease (PCAD) brain. Mech Ageing Dev 132: 443-448.
- Maynard S, Fang EF, Scheibye-Knudsen M, Croteau DL, Bohr VA (2015) DNA Damage, DNA Repair, Aging, and Neurodegeneration. Cold Spring Harb Perspect Med 5(10).
- Moreira PI, Nunomura A, Nakamura M, Takeda A, Shenk JC, et al. (2008) Nucleic acid oxidation in Alzheimer disease. Free Radic Biol Med 44: 1493-1505.
- Weissman L, de Souza-Pinto NC, Stevnsner T, Bohr VA (2007) DNA repair, mitochondria, and neurodegeneration. Neuroscience 145: 1318-1329.
- Gueven N, Chen P, Nakamura J, Becherel OJ, Kijas AW, et al. (2007) A subgroup of spinocerebellar ataxias defective in DNA damage responses. Neuroscience 145: 1418-1425.
- Lee Y, McKinnon PJ (2007) Responding to DNA double strand breaks in the nervous system. Neuroscience 145: 1365-1374.
- Bensimon A, Aebersold R, Shiloh Y (2011) Beyond ATM: the protein kinase landscape of the DNA damage response. FEBS Lett 585: 1625-1639.
- Lees-Miller SP, Meek K (2003) Repair of DNA double strand breaks by non-homologous end joining. Biochimie 85: 1161-1173.
- de Vries E, van Driel W, Bergsma WG, Arnberg AC, van der Vliet PC (1989) HeLa nuclear protein recognizing DNA termini and translocating on DNA forming a regular DNA-multimeric protein complex. J Mol Biol 208: 65-78.
- Mimori T, Hardin JA (1986) Mechanism of interaction between Ku protein and DNA. J Biol Chem 261: 10375-10379.
- Carter T, Vancurova I, Sun I, Lou W, DeLeon S (1990) A DNA-activated protein kinase from HeLa cell nuclei. Mol Cell Biol 10: 6460-6471
- Jackson SP, MacDonald JJ, Lees-Miller S, Tjian R (1990) GC box binding induces phosphorylation of Sp1 by a DNA-dependent protein kinase. Cell 63: 155-165.
- Liang F, Romanienko PJ, Weaver DT, Jeggo PA, Jasin M (1996) Chromosomal double-strand break repair in Ku80-deficient cells. Proc Natl Acad Sci U S A 93: 8929-8933.
- Satoh MS, Lindahl T (1992) Role of poly(ADP-ribose) formation in DNA repair. Nature 356: 356-358.
- Walker JR, Corpina RA, Goldberg J (2001) Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair. Nature 412: 607-614.
- Drouet J, Delteil C, Lefrancois J, Concannon P, Salles B, et al. (2005) DNA-dependent protein kinase and XRCC4-DNA ligase IV mobilization in the cell in response to DNA double strand breaks. J Biol Chem 280: 7060-7069.
- Dobbs TA, Tainer JA, Lees-Miller SP (2010) A structural model for regulation of NHEJ by DNA-PKcs autophosphorylation. DNA Repair (Amst) 9: 1307-1314.
- Nagasawa H, Little JB, Lin YF, So S, Kurimasa A, et al.(2011) Differential role of DNA-PKcs phosphorylations and kinase activity in radiosensitivity and chromosomal instability. Radiat Res 175: 83-89.
- Reddy YV, Ding Q, Lees-Miller SP, Meek K, Ramsden DA (2004) Non-homologous end joining requires that the DNA-PK complex undergo an autophosphorylation-dependent rearrangement at DNA ends. J Biol Chem 279: 39408-39413.
- Critchlow SE, Jackson SP (1998) DNA end-joining: from yeast to man. Trends Biochem Sci 23: 394-398.
- Lieber MR (1999) The biochemistry and biological significance of nonhomologous DNA end joining: an essential repair process in multicellular eukaryotes. Genes Cells 4: 77-85
- Pastink A, Eeken JC, Lohman PH (2001) Genomic integrity and the repair of double-strand DNA breaks. Mutat Res 480-481: 37-50.
- Rothkamm K, Kruger I, Thompson LH, Lobrich M (2003) Pathways of DNA double-strand break repair during the mammalian cell cycle. Mol Cell Biol 23: 5706-5715.
- Kienker LJ, Shin EK, Meek K (2000) Both V(D)J recombination and radioresistance require DNA-PK kinase activity, though minimal levels suffice for V(D)J recombination. Nucleic Acids Res 28: 2752-2761.
- Oksenych V, Kumar V, Liu X, Guo C, Schwer B, et al. (2013) Functional redundancy between the XLF and DNA-PKcs DNA repair factors in V(D)J recombination and nonhomologous DNA end joining. Proc Natl Acad Sci U S A 110: 2234-2239.
- Lieber MR, Ma Y, Pannicke U, Schwarz K (2003) Mechanism and regulation of human non-homologous DNA end-joining. Nat Rev Mol Cell Biol 4: 712-720.
- Greenblatt MS, Grollman AP, Harris CC (1996) Deletions and insertions in the p53 tumor suppressor gene in human cancers: confirmation of the DNA polymerase slippage/misalignment model. Cancer Res 56: 2130-2136.
- Korr H (1980) Proliferation of different cell types in the brain. Adv Anat Embryol Cell Biol 61: 1-72.c
- Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20: 570-577.
- Rao KS (2007) DNA repair in aging rat neurons. Neuroscience 145: 1330-1340.
- Rass U, Ahel I, West SC (2007) Defective DNA repair and neurodegenerative disease. Cell 130: 991-1004.
- Sekiguchi JM, Gao Y, Gu Y, Frank K, Sun Y, et al. (1999) Nonhomologous end-joining proteins are required for V(D)J recombination, normal growth, and neurogenesis. Cold Spring Harb Symp Quant Biol 64: 169-181.
- McKinnon PJ, Caldecott KW (2007) DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 8: 37-55.
- Yang Y, Herrup K (2005) Loss of neuronal cell cycle control in ataxia-telangiectasia: a unified disease mechanism. J Neurosci 25: 2522-2529.
- Krantic S, Mechawar N, Reix S, Quirion R (2005) Molecular basis of programmed cell death involved in neurodegeneration. Trends Neurosci 28: 670-676.
- Kruman, II, Wersto RP, Cardozo-Pelaez F, Smilenov L, Chan SL, et al. (2004) Cell cycle activation linked to neuronal cell death initiated by DNA damage. Neuron 41: 549-561.
- McMurray CT (2005) To die or not to die: DNA repair in neurons. Mutat Res 577: 260-274.
- Yang Y, Geldmacher DS, Herrup K (2001) DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 21: 2661-2668.
- Shen C, Lancaster CS, Shi B, Guo H, Thimmaiah P, et al. (2007) TOR signaling is a determinant of cell survival in response to DNA damage. Mol Cell Biol 27: 7007-7017.
- Yurov YB, Vorsanova SG, Iourov IY (2011) The DNA replication stress hypothesis of Alzheimer's disease. Sci World J 11: 2602-2612.
- Bester AC, Roniger M, Oren YS, Im MM, Sarni D, et al. (2011) Nucleotide deficiency promotes genomic instability in early stages of cancer development. Cell 14: 435-446.
- Burhans WC, Weinberger M (2007) DNA replication stress, genome instability and aging. Nucleic Acids Res 35: 7545-7556.
- Chen J, Cohen ML, Lerner AJ, Yang Y, Herrup K (2010) DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease. Mol Neurodegener 5: 60.
- Liu S, Opiyo SO, Manthey K, Glanzer JG, Ashley AK, et al. (2012) Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress. Nucleic Acids Res.
- Buisson R, Boisvert JL, Benes CH, Zou L (2015) Distinct but Concerted Roles of ATR, DNA-PK, and Chk1 in Countering Replication Stress during S Phase. Mol Cell 59: 1011-1024.
- Munoz DP, Kawahara M, Yannone SM (2013) An autonomous chromatin/DNA-PK mechanism for localized DNA damage signaling in mammalian cells. Nucleic Acids Res 41: 2894-2906.
- Smith GC, Jackson SP (1999) The DNA-dependent protein kinase. Genes Dev 13: 916-934.
- Pandita TK (2001) The role of ATM in telomere structure and function. Radiat Res 156: 642-647.
- Vogel H, Lim DS, Karsenty G, Finegold M, Hasty P (1999) Deletion of Ku86 causes early onset of senescence in mice. Proc Natl Acad Sci U S A 96: 10770-10775.
- Shackelford DA, Tobaru T, Zhang S, Zivin JA (1999) Changes in expression of the DNA repair protein complex DNA-dependent protein kinase after ischemia and reperfusion. J Neurosci 19: 4727-4738.
- Shackelford DA (2006) DNA end joining activity is reduced in Alzheimer's disease. Neurobiol Aging 27: 596-605.
- Simpson JE, Ince PG, Haynes LJ, Theaker R, Gelsthorpe C, et al. (2010) Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain. Neuropathol Appl Neurobiol 36: 25-40.
- Davydov V, Hansen LA, Shackelford DA (2003) Is DNA repair compromised in Alzheimer's disease? Neurobiol Aging 24: 953-968.
- Kanungo J (2013) DNA-dependent protein kinase and DNA repair: relevance to Alzheimer's disease. Alzheimers Res Ther 5: 13.
- Raman M, Earnest S, Zhang K, Zhao Y, Cobb MH (2007) TAO kinases mediate activation of p38 in response to DNA damage. EMBO J 26: 2005-2014.
- Cardinale A, Racaniello M, Saladini S, De Chiara G, Mollinari C, et al.(2012) Sublethal doses of beta-amyloid peptide abrogate DNA-dependent protein kinase activity. J Biol Chem 287: 2618-2631
- Grune T, Reinheckel T, Davies KJ (1997) Degradation of oxidized proteins in mammalian cells. FASEB J 11: 526-534.
- Nystrom T (2005) Role of oxidative carbonylation in protein quality control and senescence. EMBO J 24: 1311-1317.
- Culmsee C, Bondada S, Mattson MP (2001) Hippocampal neurons of mice deficient in DNA-dependent protein kinase exhibit increased vulnerability to DNA damage, oxidative stress and excitotoxicity. Brain Res Mol Brain Res 87: 257-262.
- Raman M, Chen W, Cobb MH (2007) Differential regulation and properties of MAPKs. Oncogene 26: 3100-3112.
- Han J, Lee JD, Bibbs L, Ulevitch RJ (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808-811.
- Chang KH, de Pablo Y, Lee HP, Lee HG, Smith MA, et al. (2010) Cdk5 is a major regulator of p38 cascade: relevance to neurotoxicity in Alzheimer's disease. J Neurochem 113: 1221-1229.
- Pandey P, Raingeaud J, Kaneki M, Weichselbaum R, Davis RJ, et al. (1996) Activation of p38 mitogen-activated protein kinase by c-Abl-dependent and -independent mechanisms. J Biol Chem 271: 23775-23779.
- Raman M, Earnest S, Zhang K, Zhao Y, Cobb MH (2007) TAO kinases mediate activation of p38 in response to DNA damage. EMBO J 26: 2005-2014.
- Reinhardt HC, Aslanian AS, Lees JA, Yaffe MB (2007) p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. Cancer Cell 11: 175-189.
- Pei JJ, Braak E, Braak H, Grundke-Iqbal I, Iqbal K, et al. (2001) Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. J Alzheimers Dis 3: 41-48.
- Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, et al. (2001) Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. J Neurochem 79: 311-318.
- Hwang DY, Cho JS, Lee SH, Chae KR, Lim HJ, et al. (2004) Aberrant expressions of pathogenic phenotype in Alzheimer's diseased transgenic mice carrying NSE-controlled APPsw. Exp Neurol 186: 20-32
- Koistinaho M, Kettunen MI, Goldsteins G, Keinanen R, Salminen A, et al.(2002) Beta-amyloid precursor protein transgenic mice that harbor diffuse A beta deposits but do not form plaques show increased ischemic vulnerability: role of inflammation. Proc Natl Acad Sci U S A 99: 1610-1615.
- Savage MJ, Lin YG, Ciallella JR, Flood DG, Scott RW (2002) Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition. J Neurosci 22: 3376-3385.
- Ghosh S, Wu MD, Shaftel SS, Kyrkanides S, LaFerla FM, et al. (2013) Sustained interleukin-1beta overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J Neurosci 33: 5053-5064.
- Zhu X, Mei M, Lee HG, Wang Y, Han J (2005) P38 activation mediates amyloid-beta cytotoxicity. Neurochem Res 30:791-796.
- Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, et al.(2007) A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer's disease mouse model. J Neuroinflammation 4: 21.
- Schnoder L, Hao W, Qin Y, Liu S, Tomic I, et al. (2016) Deficiency of Neuronal p38alpha MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1. J Biol Chem 291: 2067-2079.
- Otth C, Mendoza-Naranjo A, Mujica L, Zambrano A, Concha, II, et al. (2003) Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease. Neuroreport 14: 2403-2409.
- Papaconstantinou J (1994) Unifying model of the programmed (intrinsic) and stochastic (extrinsic) theories of aging. The stress response genes, signal transduction-redox pathways and aging. Ann N Y Acad Sci 719: 195-211.
- Sohal RS, Dubey A (1994) Mitochondrial oxidative damage, hydrogen peroxide release, and aging. Free Radic Biol Med 16(5): 621-626.
- Sajan FD, Martiniuk F, Marcus DL, Frey WH, 2nd, Hite R, et al. (2007) Apoptotic gene expression in Alzheimer's disease hippocampal tissue. Am J Alzheimers Dis Other Demen 22: 319-328.
- Ferrer I, Segui J, Planas AM (1996) Amyloid deposition is associated with c-Jun expression in Alzheimer's disease and amyloid angiopathy.Neuropathol Appl Neurobiol 22: 521-526
- Anderson AJ, Pike CJ, Cotman CW (1995) Differential induction of immediate early gene proteins in cultured neurons by beta-amyloid (A beta): association of c-Jun with A beta-induced apoptosis. J Neurochem 65: 1487-1498.
- Kihiko ME, Tucker HM, Rydel RE, Estus S (1999) c-Jun contributes to amyloid beta-induced neuronal apoptosis but is not necessary for amyloid beta-induced c-jun induction. J Neurochem 73: 2609-2612
- Sun A, Liu M, Nguyen XV, Bing G (2003) P38 MAP kinase is activated at early stages in Alzheimer's disease brain. Exp Neurol 183: 394-405.
- Xie Z, Smith CJ, Van Eldik LJ (2004) Activated glia induce neuron death via MAP kinase signaling pathways involving JNK and p38. Glia 45: 170-179.
- Zhu X, Rottkamp CA, Boux H, Takeda A, Perry G, et al. (2000) Activation of p38 kinase links tau phosphorylation, oxidative stress, and cell cycle-related events in Alzheimer disease. J Neuropathol Exp Neurol 59: 880-888.
- Reynolds CH, Betts JC, Blackstock WP, Nebreda AR, Anderton BH (2000) Phosphorylation sites on tau identified by nanoelectrospray mass spectrometry: differences in vitro between the mitogen-activated protein kinases ERK2, c-Jun N-terminal kinase and P38, and glycogen synthase kinase-3beta. J Neurochem 74: 1587-1595.
- Sheng JG, Jones RA, Zhou XQ, McGinness JM, Van Eldik LJ, et al. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 39: 341-348.
- Saiz-Sanchez D, Ubeda-Banon I, de la Rosa-Prieto C, Argandona-Palacios L, Garcia-Munozguren S, et al. (2010) Somatostatin, tau, and beta-amyloid within the anterior olfactory nucleus in Alzheimer disease. Exp Neurol 223: 347-350.
- Li S, Jin M, Koeglsperger T, Shepardson NE, Shankar GM, et al. (2011) Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J Neurosci 31: 6627-6638.
- Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci 24: 3370-3378.
- Ittner AA, Gladbach A, Bertz J, Suh LS, Ittner LM (2014) p38 MAP kinase-mediated NMDA receptor-dependent suppression of hippocampal hypersynchronicity in a mouse model of Alzheimer's disease. Acta Neuropathol Commun 2: 149.
- Fabian MA, Biggs WH 3rd, Treiber DK, Atteridge CE, Azimioara MD, et al. (2005) A small molecule-kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23: 329-336
- Menon MB, Dhamija S, Kotlyarov A, Gaestel M (2015) The problem of pyridinyl imidazole class inhibitors of MAPK14/p38alpha and MAPK11/p38beta in autophagy research. Autophagy 11: 1425-1427.
- Ittner A, Chua SW, Bertz J, Volkerling A, van der Hoven J, et al. (2016) Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer's mice. Science 354: 904-908.
- Mimori T, Hardin JA, Steitz JA (1986) Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. J Biol Chem 261: 2274-2278.
- Le Romancer M, Reyl-Desmars F, Cherifi Y, Pigeon C, Bottari S, et al. (1994) The 86-kDa subunit of autoantigen Ku is a somatostatin receptor regulating protein phosphatase-2A activity. J Biol Chem 269: 17464-17468.
- Pucci S, Bonanno E, Pichiorri F, Mazzarelli P, Spagnoli LG (2004) The expression and the nuclear activity of the caretaker gene ku86 are modulated by somatostatin. Eur J Histochem 48: 103-110.
- Sun KH, de Pablo Y, Vincent F, Shah K (2008) Deregulated Cdk5 promotes oxidative stress and mitochondrial dysfunction. J Neurochem 107: 265-278.