FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4225288591> ?p ?o ?g. }

• W4225288591 abstract "Review2 May 2022Open Access Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease Gwyneth Welch Gwyneth Welch orcid.org/0000-0003-1635-1190 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA Search for more papers by this author Li-Huei Tsai Corresponding Author Li-Huei Tsai [email protected] orcid.org/0000-0003-1262-0592 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA Search for more papers by this author Gwyneth Welch Gwyneth Welch orcid.org/0000-0003-1635-1190 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA Search for more papers by this author Li-Huei Tsai Corresponding Author Li-Huei Tsai [email protected] orcid.org/0000-0003-1262-0592 Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA Search for more papers by this author Author Information Gwyneth Welch1,2 and Li-Huei Tsai *,1,2 1Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA 2Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA *Corresponding author. Tel: +617 324 1660; E-mail: [email protected] EMBO Reports (2022)23:e54217https://doi.org/10.15252/embr.202154217 PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan. While newer research has shown that DNA breaks and mutations may facilitate neuron diversity during development and neuronal function throughout life, a wealth of evidence indicates deficient DNA damage repair underlies many neurological disorders, especially age-associated neurodegenerative diseases. Recently, efforts to clarify the molecular link between DNA damage and neurodegeneration have improved our understanding of how the genomic location of DNA damage and defunct repair proteins impact neuron health. Additionally, work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease. Introduction Post-mitotic neurons are the basic cellular unit of the nervous system. Their function controls primary aspects of human physiology, including movement, breathing, and heart rate, as well as higher order processes such as memory and attentional control. However, as a largely non-renewable resource, neurons must perform these essential tasks while also maintaining their cellular and genomic integrity over many decades of life. To survive the inexorable passage of time, neurons are equipped with accurate and efficient DNA damage response (DDR) pathways. Defective DDR pathways can result in toxic genomic rearrangements, transcriptional dysregulation, and the accumulation of unrepaired lesions (Hoeijmakers, 2009; Madabhushi et al, 2014; Chow & Herrup, 2015; McKinnon, 2017; Tubbs & Nussenzweig, 2017). These insults ultimately push cellular fate toward apoptosis, senescence, or uncontrolled cell division, all of which are hallmarks of age-associated disease (Hoeijmakers, 2009; Madabhushi et al, 2014; Chow & Herrup, 2015; McKinnon, 2017; Tubbs & Nussenzweig, 2017). We can appreciate the value of neuron viability in particular through the devastating effects of neurodegenerative diseases, which strip individuals of their memories, motor control, and autonomy. As of 2017, neurologic diseases are the third leading cause of death in the United States and the fifth leading cause of death world-wide (GBD, 2017 US Neurological Disorders Collaborators, 2021; GBD Compare|IHME Viz Hub). A well-established link exists between DNA damage and neurodegenerative diseases. In many cases, DNA damage seems to be one of the earliest indicators of neuropathology, suggesting it may be an initiating lesion of toxicity (Chow & Herrup, 2015; Simpson et al, 2015, 2016; Shanbhag et al, 2019). Recently, numerous findings have helped clarify the mechanisms by which DNA damage may mediate neuronal dysfunction. Broadly, these are lessons learned through both DNA damage repair disorders and models of age-associated neurodegenerative diseases. Additionally, through the advancement of sequencing techniques to map DNA lesions, rearrangements, and mutations, we are just beginning to appreciate the significance of a lesion’s genomic location in relation to its effect on neuronal activity and, ultimately, degeneration (Lodato et al, 2015, 2018; Wei et al, 2016; McConnell et al, 2017; Reid et al, 2021; Rodin et al, 2021; Wu et al, 2021). Finally, while both neuroinflammation and DNA damage are considered hallmarks and mediators of neurodegeneration, the mechanistic relationship between the two has yet to be fully realized. To this end, concepts from senescence cell biology are helping us inform how one might feed into the other (Bussian et al, 2018; Musi et al, 2018; Chow et al, 2019; Zhang et al, 2019; Gillispie et al, 2021). Here, we will cover the recent advances made in each of these subgenres of disease research and how they enhance our understanding of neuronal function and degeneration. The DNA damage response (DDR) Our genome continually incurs damage via exogenous agents and endogenous metabolic byproducts. In response to the constant onslaught of genomic lesions, mammalian cells have developed a myriad of DNA damage response (DDR) pathways, each specializing in the detection and correction of a different type of lesion. Although each pathway recruits different proteins and repair enzymes, the basic DDR format remains the same. Lesions are first detected, then they are processed and/or excised by a nuclease. Lastly, a polymerase synthesizes new DNA to replace the missing nucleotides, and a ligase seals the resulting nick together. The following section briefly summarizes DNA lesions and their corresponding DDR pathway. Single-Strand Breaks (SSBs) While many different types of genomic injuries can occur, the majority ultimately manifest in the form of single-strand breaks (SSBs). This is largely by virtue of reactive oxygen species (ROS), which attack DNA to form oxidized bases and abasic sites (Lindahl & Barnes, 2000; Madabhushi et al, 2014; Tubbs & Nussenzweig, 2017). ROS-mediated DNA damage is greatest in the nervous system(Nakamura & Swenberg, 1999), likely because neurons exhibit substantial mitochondrial respiration, consuming approximately 20% of the body’s available oxygen(Attwell & Laughlin, 2001). ROS can generate SSBs directly through attacking the DNA backbone or indirectly through the generation of other DNA modifications whose repair requires transient break formation. One of the most abundant ROS-mediated DNA modifications is 8-oxo-7,8-dihydroguanine (8oxoG), a non-bulky lesion whose presence can dysregulate gene transcription and whose erroneous repair results in mutagenesis, a major contributor to aging and disease. Non-bulky base modifications such as 8oxoG are resolved through base excision repair (BER), wherein a base-specific glycosylase detects and removes the damaged base, and the backbone is removed by apurinic/apyrimidinic endonuclease 1 (APE1) to generate an intermediate SSB. From here, the SSB can be resolved either through short-patch SSB repair (sp-SSBR) or long-patch SSBR (lp-SSBR). In short patch SSBR, polymerase β (POLβ) fills in the missing nucleotide and ligase III (LIG3) seals the nick. The alternative lp-SSBR replaces larger stretches of DNA (2-13 nucleotides), utilizing flap endonuclease 1 (FEN1), proliferating cell nuclear antigen (PCNA), and polymerase δ/ε (POL δ/ε) to open and replace the broken DNA strand. Ligase I (LIGI) then seals the nick. In contrast to smaller base lesions, helix-distorting bulky lesions (which are most commonly caused by UV exposure) are detected by their steric distortion rather than their specific chemical structure. For example, bulky lesions are detected during transcription when their presence stalls RNA polymerase II, which with the help of proteins CSA and CSB (also known as ERCC6 and ERCC8, respectively) initiates transcription-coupled nucleotide excision repair (TC-NER). In non-transcribed or inactive regions of the genome, bulky lesions are detected by the XPC-RAD23B-CEN2 complex, which initiates global genomic NER (GG-NER). Beyond the mechanism of their initial detection, TC-NER and GG-NER share the same pathway. The transcription factor complex TFIIH is recruited to the lesion and opens up the DNA, further recruiting other NER repair factors to form a pre-incision complex. The damaged nucleotide is removed by ERCC1-XPF and XPG, generating an SSB. New DNA is synthesized by POLβ/δ/ε and then sealed by LIG1 or LIG3. Apart from ROS, direct SSBs can also be generated by aborted topoisomerase I (TOP1) activity, which occurs when TOP1-initated breaks meant to relax supercoiled DNA are not resolved. These persisting breaks are termed TOP1 DNA cleavage complexes (Top1cc) (El-Khamisy et al, 2005). Top1cc accumulation poses a significant threat to the nervous system. First, oxidative DNA damage has been shown to impede Top1cc resolution (Daroui et al, 2004), making neurons particularly sensitized to aborted TOP1 activity. Second, individuals with defunct Tyrosyl-DNA Phosphodiesterase 1 (TDP1), the SSB repair enzyme responsible for resolving Top1ccs, develop spinocerebellar ataxia with axonal neuropathy (SCAN1). This genetic disease is primarily defined by nervous system deficits such as ataxia, neuropathy, and cerebellar atrophy (Takashima et al, 2002; El-Khamisy et al, 2005). Double-Strand Breaks (DSBs) While SSBs are the more common form of DNA damage, double-strand breaks (DSBs) have the higher potential for toxicity. Indeed, it is popularly cited that just one DSB can induce cell cycle arrest and subsequent apoptosis (Huang et al, 1996). However, despite their toxicity, DSBs have also been shown to play important roles in cell physiology. For example, DSBs are required for T-cell receptor and antibody diversity, chromosomal recombination during meiosis, and in the case of neurons, assist in the expression of immediate early genes (Fig 1) (Suberbielle et al, 2013; Madabhushi et al, 2015; Alt & Schwer, 2018). Figure 1. Sources of DNA damage in the brain Transcriptional activities can result in topoisomerase cleavage complexes, which lead to the induction of SSBs or DSBs depending upon the topoisomerase in question. Additionally, metabolic activity by mitochondria generate ROS, which can scar DNA bases with oxidative modifications. Although less common in the adult brain, cell division is also a source of DNA damage. Proliferation increases the chance of replication fork and transcription complex collision, thereby inducing DSBs. In the developing brain, this is a particular risk for NPCs, which harbor increased translocations in long genes (where these collisions are most likely to occur) important for neuronal function. Cognitively demanding tasks recruit specific neuronal ensembles whose plasticity is highly dependent upon immediate early gene transcription. Therefore, neurons generate topoisomerase II-mediated DSBs in response to learning and memory. Finally, the proteins responsible for various neurodegenerative diseases have also been found to play roles in DNA damage detection and repair. (Created with BioRender.com). Download figure Download PowerPoint While replication is likely the primary cause of DSBs in cycling cells, postmitotic neurons presumably incur the majority of their DSBs through transcriptional activity. SSBs may form DSBs through their collision with the transcriptional machinery and replication forks, or through their close proximity to another SSB. DSBs are also directly generated by transcription (Cannan & Pederson, 2016), whereby topoisomerase II (TOP2) induces transient DSBs to relieve torsional stress and facilitate gene expression. These Top2 cleavage complexes (Top2ccs) are usually resolved immediately by Tyrosyl-DNA Phosphodiesterase 2 (TDP2). Similar to TDP1, mutations in TDP2 result in a rare neurological disease termed spinocerebellar ataxia autosomal recessive 23 (SCAR23), further underscoring the potential toxicity of topoisomerase-induced DNA damage in the nervous system (Zagnoli-Vieira et al, 2018; Gómez-Herreros et al, 2014: 2; Errichiello et al, 2020). There are two methods of DSB repair: non-homologous end joining (NHEJ) and homologous recombination (HR). HR is considered an error-free method of DSB repair by which resected DNA strands utilize their sister chromatid as a template for DNA synthesis. First, the MRN (MRE11, RAD50, NBS1) complex binds to either side of the DSB to facilitate end resection by nucleases and helicases, including C-terminal binding protein-interacting protein (CtIP), Exonuclease 1 (EXO1), DNA replication helicase/nuclease 2 (DNA2), Werner syndrome helicase (WRN), and Bloom syndrome helicase (BLM). The resulting ssDNAs are coated by replication protein A (RPA) and RAD51, forming nucleoprotein filaments that invade the sister chromatid to look for sequence homologies. New DNA is then synthesized by a polymerase and ligated with LIG1 or LIG3. Because HR requires sister chromatids, this pathway can only occur in cycling cells during or following S phase. In contrast, NHEJ operates in all phases of the cell cycle and thus is the only DSB repair pathway available to post-mitotic cells. In canonical NHEJ, DSBs are first bound on either end by KU70/80 and DNA-dependent protein kinase (DNA-PK), then directly ligated back together with Ligase IV (LIG4), X-Ray Repair Cross Complementing 4 (XRCC4), and XRCC4-like factor (XLF). In an alternate form of NHEJ (alt-NHEJ), the broken strands are resected with the same nucleases and helicases used for HR (CtIP, EXO1, DNA2, BLM, WRN), resulting in single-strand overhangs at either side of the break site. These overhangs then anneal at microhomologies, which are small stretches of complementary DNA, usually 5–20 bp long. Polymerase θ (POLθ) synthesizes new DNA which is then ligated by LIG3. Yet another alternative DSB repair pathway, termed single-strand annealing (SSA), searches for even larger homologies (> 25 bp). RAD52 mediates the annealing of resected DNA at these larger homologous sequences, and the resulting DNA flaps are excised by ERCC1-XPF. Both alt-NHEJ and SSA are inherently error-prone, as deletions of DNA and translocations must occur to facilitate strand annealing. SSB and DSB sensing Following break induction, chromatin is rapidly modified by DNA damage sensors to facilitate the recruitment of DNA repair proteins. Poly(ADP-ribose) polymerase 1 (PARP1) and Ataxia telangectasia mutated (ATM) are two major sensors of SSBs and DSBs. PARP1 senses both SSBs and DSBs, rapidly generating poly(ADP-ribose) (PAR) chain scaffolds (PARylation) on itself and other target proteins to recruit DNA repair proteins and relax chromatin at break sites. PARylation by PARP1 recruits X-Ray Repair Cross Complementing 1 (XRCC1) which is a crucial stabilizer for end-processing enzymes POLβ and LIG3. PARylation also facilitates MRN recruitment at DSBs. Similarly, following its activation by the MRN complex at DSB sites, the protein kinase ATM phosphorylates numerous downstream substrates such as histone variant H2A.X, checkpoint kinase 2 (CHK2), and p53 to initiate DSB repair, cell cycle arrest, and apoptosis, respectively. In particular, phosphorylation of H2A.X (γH2AX) by ATM is a critical post-translational modification, flanking DSB sites more than 500 kb upstream and downstream to form γH2AX foci, which function as docking sites for chromatin remodelers and DNA repair proteins. Neurotoxicity associated with DNA damage The nervous system is particularly sensitive to loss-of-function mutations in DNA repair proteins. The explanation for this sensitivity may lie in the hallmarks of neuronal identity. That is, neurons perform transcriptionally and energetically demanding cellular functions and are post-mitotic and long-lived. The consequence of these features is elevated ROS byproducts, exclusion of error-free HR repair, age-associated decline in DNA repair enzyme efficiency, and an overall increased chance of somatic mutation. This is not to say that other cell types in the nervous system (i.e., astrocytes, oligodendrocytes, and microglia) are not susceptible to DNA damage. Indeed, DNA damage in glia plays demonstrable roles in neurodegeneration, as we will discuss later. However, compared to neurons, glial cells are replaceable, have lower energy requirements, and, in some cases, are able to re-enter the cell cycle, thus facilitating DNA repair. Combined, these features reduce the burden of DNA damage toxicity in glia. Therefore, in the following sections, we take a neuro-centric approach to interpreting the effects of DNA damage on the nervous system. Functional roles for DNA damage in neuronal activity and development could lead to dysfunction later in life Another reason why neurons are so susceptible to genomic toxicity stems from the fact that DNA breaks seem to serve a functional role in neuronal activity. Stimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate-early genes (Fig 1) (Madabhushi et al, 2015; Stott et al, 2021). Even simply introducing a mouse to a new environment is quickly followed by the induction of DSBs in neurons (Suberbielle et al, 2013, 2015). These activity-induced DSBs are hypothesized to facilitate the expression of immediate early genes through the rapid resolution of topological constraints at their transcription start sites. Previously, to identify the induction of DSBs at immediate-early gene promoters, researchers have utilized γH2AX chromatin immunoprecipitation (ChIP) sequencing (Madabhushi et al, 2015; Stott et al, 2021), which generates broad peaks associated with DSB detection. More recently developed technologies may help improve the resolution of activity-associated break induction in neurons (Rybin et al, 2021). For example, a DSB-mapping technique known as END-seq was recently used to identify strand breaks in human induced pluripotent stem cell (iPSC)-derived neurons, resulting in the finding that enhancers are hotspots for SSBs (Canela et al, 2016; Wu et al, 2021). Newer break-mapping techniques include single nucleotide precision, Break Labeling In Situ and Sequencing (BLISS) for DSBs (Yan et al 2017) and single-strand break mapping at nucleotide genome level (SSiNGLe) for both SSBs and DSBs (Cao et al, 2019). However, the utility of these techniques has yet to be evaluated, as currently neither has been used to analyze the location of DNA breaks in neurons in physiological or pathological conditions. Crucially, while DNA breaks may serve a physiological function in learning and memory, their recurrence in neuron regulatory sequences makes these regions extremely vulnerable to mutation and translocation. One can imagine that over time, erroneous DSB repair could lead to mutations that result in transcriptomic dysfunction, which could further manifest at the cellular level as impaired synaptic signaling. In line with this hypothesis, DNA repair mapping reveals that postmitotic neurons do indeed accumulate breaks in regulatory elements associated with neuronal function (Fig 2) (Reid et al, 2021; Wu et al, 2021). Figure 2. DNA lesions and mutations identified in neural genes and the techniques used to map them While all cell types incur DNA damage and mutations, neurons in particular are susceptible due to activity-induced transcription. Immediate-early genes and other neuronal genes that enable synaptic function are highly transcribed. Accordingly, they accumulate DNA lesions and mutations in their gene body (Wei et al, 2016) and regulatory regions (Lodato et al, 2015; Reid et al, 2021; Wu et al, 2021). The induction of DSBs in the promoters of immediate-early genes facilitates gene expression (Madabhushi et al, 2015). Over time, these insults may impair neural function (Lu et al, 2004; Lodato et al, 2018; Pao et al, 2020). (Created with BioRender.com). Download figure Download PowerPoint In addition to postmitotic activity, it is clear that somatic mutations induced by erroneous DNA damage repair or transposable elements are a common feature of neural development, giving rise to neuron diversity through genomic mosaicism (McConnell et al, 2013; Alt & Schwer, 2018; Lodato & Walsh, 2019). While most mutations are likely to be neutral, work has shown that some may underly neurodevelopmental and neurodegenerative disease. For example, work mapping translocations in iPSC-derived neural precursor cells (NPCs) under replicative stress reveal that DSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia (Wei et al, 2016, 2018; Wang et al, 2020). This mapping was accomplished through a technique known as linear amplification-mediated high-throughput, genome-wide, translocation sequencing (LAM-HTGTS). Using this technique, endogenous DSBs are identified based on their translocation to a “bait” DSB located at a specific region in the genome. Furthermore, a study performing whole exome sequencing of hippocampal tissue from individuals with Alzheimer’s disease (AD) revealed that somatic single nucleotide variations (SNVs) increase with age and are enriched in genes that regulate tau phosphorylation (Park et al, 2019). Accumulation of SNVs at neurodegeneration risk genes could potentially increase risk of disease development. DNA repair syndromes as proxies for aging and neurodegenerative disease Some of the most long-standing evidence for the role of DNA damage in aging and neurodegeneration stems from inheritable DNA damage disorders, which frequently present with neurologic abnormalities. With the exception of AOA5, which seems to have manifested exclusively in adults so far (Hoch et al, 2017: 1; O’Connor et al, 2018: 1), the majority of DNA damage disorders typically present in early childhood. Why then would these disorders support the hypothesis that DNA damage plays critical roles in aging and neurodegeneration? First, as discussed in the previous section, we must acknowledge the pivotal role of DNA damage repair in neurodevelopment, a period in which the rapid proliferation of NPCs results in profound transcriptional and replication-associated DNA damage. Deficient DNA damage repair in these vulnerable NPCs results in developmental abnormalities such as microcephaly, which is a feature of many DNA damage disorders. However, many DNA damage disorders are also defined by age-associated pathologies such as progressive brain atrophy and peripheral neuropathy. In these cases, it is likely that post-mitotic neurons are bearing the brunt of the DNA repair deficit. Thus, whether the resulting pathologies of a DNA repair deficit are developmental or age-associated likely depends on both the brain cell type composition at the time and the selective vulnerabilities of different neuronal subtypes to different repair deficits. Finally, the pathogenic load of a loss-of-function mutation accelerates the development of age-associated pathology, which may account for a DNA damage disorder presenting in childhood rather than later in life. In contrast, an individual devoid of DNA repair mutations must experience the progressive stress of aging (i.e. damage accumulation, oxidative stress, declining DNA repair enzyme efficiency) in order to recapitulate the pathogenic load of a DNA damage disorder. In the following subsections, we highlight two recently developed models of DNA damage disorders (one driven by mutant XRCC1, and the other by mutant ATM, and APTX) that have clarified mechanisms of DNA damage-mediated neuronal dysfunction. Neurological diseases caused by SSBR mutations To date, loss-of-function mutations in SSBR proteins have manifested exclusively as neurodegenerative syndromes. Ataxia with Oculomotor Apraxia types 1 and 4 (AOA1, AOA4) are caused by mutations in DNA end-processing enzymes Aprataxin (APTX) and Polynucleotide Kinase 3′-Phosphatase (PNKP) respectively. As their names denote, both are progressive neurodegenerative diseases typified by cerebellar atrophy, ataxia, and oculomotor apraxia. SCAN1, caused by defective TDP1, is a similar neurodegenerative syndrome additionally characterized by peripheral neuropathy (Takashima et al, 2002; El-Khamisy et al, 2005). More recently, mutations have been identified in XRCC1 (Hoch et al, 2017; O’Connor et al, 2018: 1), the protein that complexes with and stabilizes all of these end-processing enzymes. Defective XRCC1 manifests in individuals as Ataxia with Oculomotor apraxia Type 5 (AOA5), another slow-progressing neurodegenerative disease. If SSBs are left unrepaired in cycling cells, they can form DSBs upon collision with DNA replication complexes (Ryan et al, 1991). Cycling cells with defective SSBR can access error-free HR during cell division to repair the resulting DSBs. However, post-mitotic neurons are not equipped with this alternate method of repair. This may explain why diseases of SSBR are exclusive to the nervous system; neurons are not able to mitigate SSB accumulation without the presence of a functioning SSBR. To this point, recent investigations into how mutant XRCC1 confers neuropathy have helped clarify the mechanisms by which defective SSBR could be neurotoxic. First, the study of patient fibroblasts from an individual with AOA5 revealed that in the absence of XRCC1, PARP1 becomes hyperactive, producing excessive amounts of poly(ADP-ribose) (Hoch et al, 2017). Unchecked PARP1 activity can induce cell death by progressive NAD+/ATP depletion and Parthanatos, a cell death signaling pathway triggered by excessive poly(ADP-ribose) (David et al, 2009). PARP1 hyperactivity was further demonstrated through conditional deletion of XRCC1 in the mouse brain, which resulted in progressive cerebellar degeneration, ataxia, seizure-like activity, and dysregulated presynaptic calcium signaling in the hippocampus (Hoch et al, 2017; Komulainen et al, 2021). The mechanisms by which PARP1 hyperactivity could mediate neurotoxicity and dysregulated presynaptic calcium signaling have been explored in an additional pair of recent publications. First, in the absence of XRCC1, PARP1 was found “trapped” at break intermediates produced during BER, thus impeding access of repair factors POLβ and LIG3 (Demin et al, 2021). This indicates XRCC1 is a crucial regulator of PARP1 activity. Second, PARP1 hyperactivity in XRCC1-deficient cells was shown to suppress transcription through the recruitment of ubiquitin protease USP3, leading to excessive deubiquitination of histone substrates (Adamowicz et al, 2021). Suppressed transcription may account for the dysregulated calcium signaling observed in neurons from XRCC1Nes-Cre mice, specifically through the suppression of genes that regulate calcium homeostasis. To this point, a separate publication revealed that iPSC-derived neurons accumulate SSBs at enhancers regulating neuronal activity (Wu et al, 2021). These SSB hotspots were identified through genome-wide mapping of DNA damage repair, dubbed SAR-seq (Synthesis After Repair), whereby EdU incorporation into break sites serves as a molecular landmark for break repair, and END-seq (Wu et al, 2021). SSB accumulation at enhancers regulating neuronal activity provides a tempting mechanistic explanation for the neurodegenerative hallmarks of SSBR syndromes. In contrast to mutations in the SSBR pathways, mutations that dysregulate the NER pathway are additionally characterized by symptoms occurring outside of the nervous system. For example, the hallmark feature of Xeroderma Pigmentosum, caused by XP gene mutations, is skin peeling and crusting due to the skin cells' inability to repair bulky DNA modifications caused by UV exposure. Only about 20–30% of XP individuals develop progressive neurodegeneration (Nouspikel, 2008). Furthermore, individuals with Cockayne Syndrome (CS), who are diagnosed based on delayed development, light sensitivity, and progeria, or Trichothiodystrophy (TTD), whose hallmark feature is brittle hair, can present with neurodevelopmental defects such as microcephaly, dysmyelination, and intellectual disability (Diderich et al, 2011). Notably, while postmitotic neurons are able to repair bulky DNA modifications in both the template and non-template strand of transcribed genes, global NER is naturally attenuated in non-transcribed regions of the genome (Nouspikel & Hanawalt, 2000; Nouspikel, 2008). Combined with the added stressor of NER mutations, this may account for the neurodegenerative phenotypes observed in XP, CS, and TTD. Neurological diseases caused by DSBR mutations One of the most well-known DDR syndromes is Ataxia telangectasia (AT), which is caused by mutations in ATM kinase. Individuals with AT exhibit profound immune deficiency and increased cancer susceptibility as well as progressive cerebellar atrophy, which results in ataxia by early childhood (McKin" @default.
• W4225288591 created "2022-05-05" @default.
• W4225288591 creator A5042440695 @default.
• W4225288591 creator A5059449657 @default.
• W4225288591 date "2022-05-02" @default.
• W4225288591 modified "2023-10-09" @default.
• W4225288591 title "Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease" @default.
• W4225288591 cites W1494866131 @default.
• W4225288591 cites W1522901791 @default.
• W4225288591 cites W1542158376 @default.
• W4225288591 cites W1542215809 @default.
• W4225288591 cites W1568134298 @default.
• W4225288591 cites W1575040108 @default.
• W4225288591 cites W1758544898 @default.
• W4225288591 cites W1783508367 @default.
• W4225288591 cites W1895398290 @default.
• W4225288591 cites W1913599140 @default.
• W4225288591 cites W1965942744 @default.
• W4225288591 cites W1967899016 @default.
• W4225288591 cites W1970227011 @default.
• W4225288591 cites W1970561675 @default.
• W4225288591 cites W1973522156 @default.
• W4225288591 cites W1976564193 @default.
• W4225288591 cites W1977069725 @default.
• W4225288591 cites W1979369962 @default.
• W4225288591 cites W1982602899 @default.
• W4225288591 cites W1991666948 @default.
• W4225288591 cites W1999744197 @default.
• W4225288591 cites W2000559850 @default.
• W4225288591 cites W2005889734 @default.
• W4225288591 cites W2006764478 @default.
• W4225288591 cites W2010355916 @default.
• W4225288591 cites W2010417927 @default.
• W4225288591 cites W2010677667 @default.
• W4225288591 cites W2019276374 @default.
• W4225288591 cites W2023532020 @default.
• W4225288591 cites W2033004300 @default.
• W4225288591 cites W2036931425 @default.
• W4225288591 cites W2038078790 @default.
• W4225288591 cites W2040829831 @default.
• W4225288591 cites W2042422091 @default.
• W4225288591 cites W2045475043 @default.
• W4225288591 cites W2046589688 @default.
• W4225288591 cites W2049448938 @default.
• W4225288591 cites W2056079743 @default.
• W4225288591 cites W2062445688 @default.
• W4225288591 cites W2072092279 @default.
• W4225288591 cites W2072358340 @default.
• W4225288591 cites W2076745180 @default.
• W4225288591 cites W2079414750 @default.
• W4225288591 cites W2080053685 @default.
• W4225288591 cites W2083922442 @default.
• W4225288591 cites W2087243986 @default.
• W4225288591 cites W2087367816 @default.
• W4225288591 cites W2088470456 @default.
• W4225288591 cites W2089038479 @default.
• W4225288591 cites W2093920124 @default.
• W4225288591 cites W2097049162 @default.
• W4225288591 cites W2097750604 @default.
• W4225288591 cites W2102430316 @default.
• W4225288591 cites W2102904926 @default.
• W4225288591 cites W2107416433 @default.
• W4225288591 cites W2109664107 @default.
• W4225288591 cites W2112451788 @default.
• W4225288591 cites W2116054786 @default.
• W4225288591 cites W2116207236 @default.
• W4225288591 cites W2116435487 @default.
• W4225288591 cites W2119098586 @default.
• W4225288591 cites W2124451653 @default.
• W4225288591 cites W2125644182 @default.
• W4225288591 cites W2127761639 @default.
• W4225288591 cites W2128916701 @default.
• W4225288591 cites W2130753450 @default.
• W4225288591 cites W2131418908 @default.
• W4225288591 cites W2135660738 @default.
• W4225288591 cites W2137903075 @default.
• W4225288591 cites W2140216668 @default.
• W4225288591 cites W2142913420 @default.
• W4225288591 cites W2147701649 @default.
• W4225288591 cites W2147930131 @default.
• W4225288591 cites W2149959669 @default.
• W4225288591 cites W2150727477 @default.
• W4225288591 cites W2152384795 @default.
• W4225288591 cites W2153825225 @default.
• W4225288591 cites W2193792657 @default.
• W4225288591 cites W2218943248 @default.
• W4225288591 cites W2237137237 @default.
• W4225288591 cites W2252783105 @default.
• W4225288591 cites W2266290735 @default.
• W4225288591 cites W2268858163 @default.
• W4225288591 cites W2274643654 @default.
• W4225288591 cites W2282960029 @default.
• W4225288591 cites W2316716290 @default.
• W4225288591 cites W2323797330 @default.
• W4225288591 cites W2342089554 @default.
• W4225288591 cites W2470223656 @default.
• W4225288591 cites W2495544654 @default.
• W4225288591 cites W2514975062 @default.
• W4225288591 cites W2562264987 @default.
• W4225288591 cites W2563186352 @default.

• next