Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

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The Relevance of G-Quadruplexes for DNA Repair

International Journal of Molecular Sciences ◽

10.3390/ijms222212599 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12599

Author(s):

Rebecca Linke ◽

Michaela Limmer ◽

Stefan Juranek ◽

Annkristin Heine ◽

Katrin Paeschke

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Genome Instability ◽

Genetic Disorders ◽

Telomere Maintenance ◽

Dna Structures ◽

G4 Dna ◽

G Quadruplex ◽

Repair Pathways

DNA molecules can adopt a variety of alternative structures. Among these structures are G-quadruplex DNA structures (G4s), which support cellular function by affecting transcription, translation, and telomere maintenance. These structures can also induce genome instability by stalling replication, increasing DNA damage, and recombination events. G-quadruplex-driven genome instability is connected to tumorigenesis and other genetic disorders. In recent years, the connection between genome stability, DNA repair and G4 formation was further underlined by the identification of multiple DNA repair proteins and ligands which bind and stabilize said G4 structures to block specific DNA repair pathways. The relevance of G4s for different DNA repair pathways is complex and depends on the repair pathway itself. G4 structures can induce DNA damage and block efficient DNA repair, but they can also support the activity and function of certain repair pathways. In this review, we highlight the roles and consequences of G4 DNA structures for DNA repair initiation, processing, and the efficiency of various DNA repair pathways.

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Genomic Instability and the Oncohistone H3K27M Drive Gliomagenesis in a Murine Model

10.21007/etd.cghs.2020.0515 ◽

2020 ◽

Author(s):

◽

Lee Pribyl ◽

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Progenitor Cells ◽

Neural Development ◽

Genome Stability ◽

Damage Accumulation ◽

Genome Instability ◽

Cortical Development ◽

Neural Cells ◽

Repair Pathways

Maintaining genome stability is crucial for human health and it is of particular importance in neural cells during early brain development. Genome maintenance occurs at two broad stages; surveillance during DNA replication and DNA damage repair in differentiating and mature cells. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects on the nervous system, including cancer. Multiple DNA repair pathways play critical roles in preventing DNA damage accumulation in stem and neural progenitor cells. The mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of this dissertation is to understand the relative contributions of key DNA repair factors that prevent tumorigenesis during cortical development. We have compared the differential effects of inhibition of homologous recombination (HR), via BRCA2-inactivation and non-homologous end-joining (NHEJ), via LIG4-inactivation towards tumorigenesis by directing their deletion specifically to early cortical progenitors using an Emx1-cre recombinase driver. We find that coincident loss of either of these repair pathways with p53 inhibition result in distinct high-grade glioma (HGG) formation resulting from elevated genome instability by DNA damage accumulation during embryogenesis. Furthermore, the presence of the oncohistone H3K27M mutation, commonly found in pediatric HGGs, enhances genome instability and accelerates cortical gliomagenesis with p53 inactivation and defective HR or NHEJ. Additionally, the H3K27M resultant gliomas showed distinctive differences in increased brain tumor penetrance and diffusion. Through RNA-sequencing and whole exome sequencing we identify upregulation of genes normally controlled by bivalent gene promoter post-translational modifications, which result in transcriptional alterations in genes important for both neural development and tumorigenesis. Mechanistically, this is done by targeting specific populations of cortical cells that are more susceptible to DNA damage and transformations that may cause additional critical mutations during a limited timeframe of early cortical development which eventually result in HGGs. We provide evidence supporting that BRCA2 functions to provide DSBR and genome stability to the early-born proliferating cortical progenitor cell population, while LIG4 provides the same function but to a lesser extent to progenitor cells and more so to post-mitotic neurons. Since, epigenetic regulation is tightly connected with neural development and differentiation, we propose the specific genes that H3K27M effects may differ depending on the time period and particular cell state from which the HGG initiates. We believe this contributes to reduced heterogeneity in glioma expression signatures with H3K27M in addition to either HR- or NHEJ-deficiency. Ultimately this work highlights the power of inducible genetically engineered mouse models as an approach to better understand the complexities of providing a connection between genome instability and gliomagenesis.

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Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽

10.3390/biology10020163 ◽

2021 ◽

Vol 10 (2) ◽

pp. 163

Author(s):

Swapnil Gupta ◽

Panpan You ◽

Tanima SenGupta ◽

Hilde Nilsen ◽

Kulbhushan Sharma

Keyword(s):

Dna Repair ◽

Neurodegenerative Diseases ◽

3D Models ◽

Model Systems ◽

Spinocerebellar Ataxias ◽

C Elegans ◽

Cellular Processes ◽

Age Related ◽

Damage Response ◽

Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

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NME3 Regulates Mitochondria to Reduce ROS-Mediated Genome Instability

International Journal of Molecular Sciences ◽

10.3390/ijms21145048 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5048

Author(s):

Chih-Wei Chen ◽

Ning Tsao ◽

Wei Zhang ◽

Zee-Fen Chang

Keyword(s):

Oxidative Stress ◽

Dna Repair ◽

Genome Stability ◽

Nuclear Dna ◽

Genome Instability ◽

Mitochondrial Fission ◽

Nucleoside Diphosphate Kinase ◽

Mitochondrial Fusion ◽

Mitochondrial Outer Membrane ◽

Mitochondrial Oxidative Stress

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family that binds to the mitochondrial outer membrane to stimulate mitochondrial fusion. In this study, we showed that NME3 knockdown delayed DNA repair without reducing the cellular levels of nucleotide triphosphates. Further analyses revealed that NME3 knockdown increased fragmentation of mitochondria, which in turn led to mitochondrial oxidative stress-mediated DNA single-strand breaks (SSBs) in nuclear DNA. Re-expression of wild-type NME3 or inhibition of mitochondrial fission markedly reduced SSBs and facilitated DNA repair in NME3 knockdown cells, while expression of N-terminal deleted mutant defective in mitochondrial binding had no rescue effect. We further showed that disruption of mitochondrial fusion by knockdown of NME4 or MFN1 also caused mitochondrial oxidative stress-mediated genome instability. In conclusion, the contribution of NME3 to redox-regulated genome stability lies in its function in mitochondrial fusion.

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The Role of Posttranslational Modifications in DNA Repair

BioMed Research International ◽

10.1155/2020/7493902 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Miaomiao Bai ◽

Dongdong Ti ◽

Qian Mei ◽

Jiejie Liu ◽

Xin Yan ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Protein Interactions ◽

Posttranslational Modifications ◽

Genome Stability ◽

Protein Localization ◽

Complex Structure ◽

Protein Protein Interactions ◽

Regulate Protein

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

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Genome Maintenance Mechanisms at the Chromatin Level

International Journal of Molecular Sciences ◽

10.3390/ijms221910384 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10384

Author(s):

Hirotomo Takatsuka ◽

Atsushi Shibata ◽

Masaaki Umeda

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Genotoxic Stress ◽

Genome Integrity ◽

Easy Access ◽

Order Structure ◽

Chromatin Modifications ◽

Level Control ◽

Regulatory Systems

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

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Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors

Immunotherapy ◽

10.2217/imt-2021-0024 ◽

2021 ◽

Vol 13 (14) ◽

pp. 1205-1213

Author(s):

Pauline Rochefort ◽

Françoise Desseigne ◽

Valérie Bonadona ◽

Sophie Dussart ◽

Clélia Coutzac ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Immune Checkpoint ◽

Genome Stability ◽

Immune Checkpoint Inhibitor ◽

Checkpoint Inhibitor ◽

Excision Repair ◽

Checkpoint Inhibitors ◽

Repair Deficiency ◽

Dna Repair Deficiency

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

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Advances and perspectives of PARP inhibitors

Experimental Hematology and Oncology ◽

10.1186/s40164-019-0154-9 ◽

2019 ◽

Vol 8 (1) ◽

Cited By ~ 15

Author(s):

Ming Yi ◽

Bing Dong ◽

Shuang Qin ◽

Qian Chu ◽

Kongming Wu ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Cells ◽

Genome Instability ◽

Single Gene ◽

High Sensitivity ◽

Lethal Effect ◽

Single Strand Break ◽

Synthetic Lethal ◽

Increased Risk

Abstract DNA damage repair deficiency leads to the increased risk of genome instability and oncogenic transformation. In the meanwhile, this deficiency could be exploited for cancer treatment by inducing excessive genome instability and catastrophic DNA damage. Continuous DNA replication in cancer cells leads to higher demand of DNA repair components. Due to the oncogenic loss of some DNA repair effectors (e.g. BRCA) and incomplete DNA repair repertoire, some cancer cells are addicted to certain DNA repair pathways such as Poly (ADP-ribose) polymerase (PARP)-related single-strand break repair pathway. The interaction between BRCA and PARP is a form of synthetic lethal effect which means the simultaneously functional loss of two genes lead to cell death, while defect in any single gene has a slight effect on cell viability. Based on synthetic lethal theory, Poly (ADP-ribose) polymerase inhibitor (PARPi) was developed aiming to selectively target cancer cells harboring BRCA1/2 mutations. Recently, a growing body of evidence indicated that a broader population of patients could benefit from PARPi therapy far beyond those with germline BRCA1/2 mutated tumors. Numerous biomarkers including homologous recombination deficiency and high level of replication pressure also herald high sensitivity to PARPi treatment. Besides, a series of studies indicated that PARPi-involved combination therapy such as PARPi with additional chemotherapy therapy, immune checkpoint inhibitor, as well as targeted agent had a great advantage in overcoming PARPi resistance and enhancing PARPi efficacy. In this review, we summarized the advances of PARPi in clinical application. Besides, we highlighted multiple promising PARPi-based combination strategies in preclinical and clinical studies.

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Obesity, DNA Damage, and Development of Obesity-Related Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms20051146 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1146 ◽

Cited By ~ 30

Author(s):

Marta Włodarczyk ◽

Grażyna Nowicka

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Dietary Habits ◽

Cell Metabolism ◽

Cancer Cell Proliferation ◽

Dna Repair Mechanisms ◽

Repair Mechanisms ◽

Risk Assessment And Prevention ◽

And Migration

Obesity has been recognized to increase the risk of such diseases as cardiovascular diseases, diabetes, and cancer. It indicates that obesity can impact genome stability. Oxidative stress and inflammation, commonly occurring in obesity, can induce DNA damage and inhibit DNA repair mechanisms. Accumulation of DNA damage can lead to an enhanced mutation rate and can alter gene expression resulting in disturbances in cell metabolism. Obesity-associated DNA damage can promote cancer growth by favoring cancer cell proliferation and migration, and resistance to apoptosis. Estimation of the DNA damage and/or disturbances in DNA repair could be potentially useful in the risk assessment and prevention of obesity-associated metabolic disorders as well as cancers. DNA damage in people with obesity appears to be reversible and both weight loss and improvement of dietary habits and diet composition can affect genome stability.

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Mutations in CREBBP and EP300 genes affect DNA repair of oxidative damage in Rubinstein-Taybi syndrome cells

Carcinogenesis ◽

10.1093/carcin/bgz149 ◽

2019 ◽

Vol 41 (3) ◽

pp. 257-266

Author(s):

Ilaria Dutto ◽

Claudia Scalera ◽

Micol Tillhon ◽

Giulio Ticli ◽

Gianluca Passaniti ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Genome Stability ◽

Oxidative Dna Damage ◽

Excision Repair ◽

Control Cell ◽

Nuclear Antigen ◽

Autosomal Dominant Disorder ◽

Cell Extracts ◽

Increased Risk

Abstract Rubinstein-Taybi syndrome (RSTS) is an autosomal-dominant disorder characterized by intellectual disability, skeletal abnormalities, growth deficiency and an increased risk of tumors. RSTS is predominantly caused by mutations in CREBBP or EP300 genes encoding for CBP and p300 proteins, two lysine acetyl-transferases (KAT) playing a key role in transcription, cell proliferation and DNA repair. However, the efficiency of these processes in RSTS cells is still largely unknown. Here, we have investigated whether pathways involved in the maintenance of genome stability are affected in lymphoblastoid cell lines (LCLs) obtained from RSTS patients with mutations in CREBBP or in EP300 genes. We report that RSTS LCLs with mutations affecting CBP or p300 protein levels or KAT activity, are more sensitive to oxidative DNA damage and exhibit defective base excision repair (BER). We have found reduced OGG1 DNA glycosylase activity in RSTS compared to control cell extracts, and concomitant lower OGG1 acetylation levels, thereby impairing the initiation of the BER process. In addition, we report reduced acetylation of other BER factors, such as DNA polymerase β and Proliferating Cell Nuclear Antigen (PCNA), together with acetylation of histone H3. We also show that complementation of CBP or p300 partially reversed RSTS cell sensitivity to DNA damage. These results disclose a mechanism of defective DNA repair as a source of genome instability in RSTS cells.

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