User:Asema24
Asema Maratova 2024 Geromics Course
Asema Maratova
Contact: asema24@unist.ac.kr
Department: Biological Science
Interest: DNA damage and repair, cancer
Asema Maratova
20225573
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" strokecolor="#156082 [3204]" strokeweight=".5pt" style="position:absolute; margin-left:185px; margin-top:2px; width:79pt; height:0; z-index:251660288" type="#_x0000_t32"><v:stroke endarrow="block" joinstyle="miter" startarrow="block"></v:stroke></v:shape> NER Iatrogenic genotoxins
Aging is a complex biological process characterized by the gradual decline in physiological functions and increased vulnerability to various diseases, including cancer. One of the key factors contributing to aging is the accumulation of DNA damage over time. DNA repair mechanisms, such as Nucleotide Excision Repair (NER), play a crucial role in maintaining genomic stability by repairing a wide range of DNA lesions. Since my research topic is related to DNA damage response pathways, specifically NER. I would like to show a connection between NER and aging. Additionally, I would like to show connection between aging and Iatrogenic genotoxins.
Part I
Firsly, lets start with NER.Understanding the relationship between aging and NER involves exploring how changes in NER efficiency contribute to the aging process and age-related diseases.
NER is a versatile DNA repair pathway responsible for detecting and removing bulky DNA lesions caused by ultraviolet (UV) radiation, chemical mutagens, and oxidative stress. These lesions can distort the DNA helix, interfering with transcription and replication. The NER process involves several steps:
Damage Recognition: NER can be initiated through two sub-pathways: Global Genomic NER (GG-NER) and Transcription-Coupled NER (TC-NER). GG-NER scans the entire genome for lesions, while TC-NER specifically targets lesions that block transcription.
Damage Excision: After lesion recognition, the DNA surrounding the damage is unwound, and a short single-stranded DNA segment containing the lesion is excised.
DNA Synthesis and Ligation:The resulting gap is filled by DNA polymerase using the undamaged strand as a template, and the newly synthesized DNA is ligated to restore the DNA backbone.
Aging and Decline in NER Efficiency
Research indicates that the efficiency of NER declines with age, which contributes to the accumulation of DNA damage. Several factors are implicated in this decline are:
Firstly, decreased expression of NER genes: The expression levels of critical NER genes, such as those encoding for the XPA, XPC, and ERCC1 proteins, have been shown to decrease with age. This reduction in gene expression leads to a lower availability of essential repair proteins, compromising the overall efficiency of the NER pathway.
Secondly, post-translational modifications:Age-related changes in post-translational modifications of NER proteins can affect their stability, localization, and interaction with other repair factors. For instance, oxidative stress can lead to the modification of repair proteins, impairing their function.
Thirdly, epigenetic changes: Epigenetic modifications, such as DNA methylation and histone acetylation, change with age and can influence the accessibility of NER machinery to damaged sites. These changes can result in reduced recruitment and assembly of repair complexes at DNA lesions.
Lastly, accumulation of senescent cells: Senescent cells, which are characterized by a permanent cell cycle arrest, accumulate with age and exhibit a senescence-associated secretory phenotype (SASP). These cells can secrete factors that promote inflammation and tissue dysfunction, indirectly affecting NER efficiency by altering the tissue microenvironment.
Implications for Age-Related Diseases
The decline in NER efficiency with age has significant implications for age-related diseases, particularly cancer and neurodegenerative disorders:
Cancer: Reduced NER activity leads to an accumulation of DNA damage, increasing the risk of mutations that can drive carcinogenesis. Age-related decline in NER is associated with a higher incidence of skin cancers, such as basal cell carcinoma and melanoma, which are linked to UV-induced DNA damage.
Neurodegenerative Diseases:Neurons are particularly susceptible to DNA damage due to their high metabolic activity and limited capacity for regeneration. Impaired NER in aging neurons contributes to the accumulation of DNA lesions, which can disrupt transcription and neuronal function, potentially leading to neurodegenerative diseases such as Alzheimer's and Parkinson's.
Understanding the relationship between aging and NER opens avenues for potential interventions aimed at enhancing DNA repair capacity and mitigating age-related decline. I can suggest the folowing potential interventions according to my research on this topic.
Gene Therapy:Introducing or upregulating key NER genes through gene therapy could help restore NER efficiency in aged cells, reducing DNA damage accumulation and its associated effects.
Pharmacological Agents: Developing drugs that enhance the activity of NER proteins or protect them from age-related modifications could improve DNA repair capacity. Antioxidants, for example, might reduce oxidative damage to NER proteins and DNA.
Lifestyle Interventions: Lifestyle factors, such as a healthy diet rich in antioxidants, and avoidance of excessive UV exposure, can help minimize DNA damage and support DNA repair mechanisms.
The relationship between aging and Nucleotide Excision Repair is a critical aspect of understanding the biological mechanisms underlying aging and age-related diseases. The decline in NER efficiency with age contributes to the accumulation of DNA damage, increasing the risk of cancer and neurodegenerative disorders. By exploring the factors that influence NER activity and developing strategies to enhance DNA repair capacity, we can potentially mitigate some of the adverse effects of aging and improve healthspan and longevity.
Part II
In my opinion, there are sufficient and diverse evidence to support a cogent argument that DNA damage plays a causal role in aging. This includes environmental/iatrogenic sources of genotoxic stress as well as spontaneous/endogenous genotoxic stress. DNA damage contributes to aging via cell autonomous events such as causing apoptosis, which depletes functional cells such as neurons, and via cell non-autonomous mechanisms such as triggering senescence which all effect neighboring cells. DNA damage, once detected should be repaired. If no repair occurs, can interfere with biological function of the cells.It can also result in mitochondrial dysfunction, impaired autophagy, metabolic changes, and the triggering of cellular. These live but physiologically altered cells are predicted to be a more potent driver of aging and disease.
The number of cancer survivors is increasing dramatically as a consequence of improved therapeutics. Unfortunetaly, these patients treated with genetoxic agents are aged rapidly. Radiation and genotoxic chemotherapy are used to kill rapidly dividing cells, like tumor cells. However, It will not directly recognize cancer cells. All cells in the body can experience genotoxic stress induced by chemotherapy/radiotherapy which later triggering aging. In my opinion, whether DNA damage is increased by exposure to genotoxins or by genetic depletion of repair mechanisms, the consequence might be the same: accelerated aging.
This supports the notion that DNA damage, regardless of whether the source is endogenous or exogenous, can be both the why and how aging occurs.
In my research, I usedcisplatin, carboplatin, and oxaliplatin which are FDA-approved platinum-based anti-tumor drugs (Genotoxins) used in chemotherapy regimens.Their therapeutic efficacy is principally attributed to the formation of DNA intrastrand and interstrand cross-links, which disrupt vital cellular processes such as DNA replication, ultimately triggering apoptosis and cell death. Despite their clinical significance, the emergence of drug resistance and adverse side effects pose substantial challenges to the efficacy and tolerability of platinum-based chemotherapy.Resistance of platinum drugs is the major drawback to the clinical success of the drug and overcoming it remains one of the main goals for the anticancer therapy.To use platinum drugs in a more targeted manner new approaches are needed to predict therapy response.Our laboratory aimed to address these challenges through the development of comprehensive ultraperformance liquid chromatography-selective ion monitoring (UPLC-SIM) assays. To quantify various types of DNA intrastrand cross-links induced by platinum drugs, including 1,2-GG, 1,2-AG, 1,3-GCG, and 1,3-GTG cross-links.One powerful approach to elucidate reactivity with DNA and to measure the persistence of platinum-DNA adducts in cells would be to determine the levels of different types of cisplatin-DNA crosslinks in genomic DNA.
I aimed to develop a complementary assay to investigate the repair kinetics of platinum intrastrand crosslinks by nucleotide excision repair (NER). For this purpose, I adapted alkaline COMET chip assays. To precisely measure NER incision rates in response to platinum drug-induced DNA-DNA breaks within G1 phase cells. Through this assay, I aimed to elucidate the important interplay between NER-mediated repair processes and the cytotoxic effects of platinum drugs.
By additionally studying the repair mechanisms associated with platinum drug therapy, I aimed to contribute to the development of more efficacious and targeted treatment strategies for overcoming platinum resistance mechanisms in cancer therapy.
Indeed, this approach may serve as a valuable tool to complement the study of DNA adduct formation and repair in cells.Additionaly, these assays can be used as a diagnostic tool to study how NER contribute to sensitivity of the cancer cells to platinum drugs. Many types of tumor, such as testicular, breast, ovarian and bladder cancer are treated with platinum drugs.
If a patient has resistance to platinum drugs, we can identify this with our therapeutic tool. There is no need to subject the patient to more genotoxic stress if the therapy will not be effective. I believe that fighting cancer means fighting aging.
Concluding remarks from Asema
For me, learning is about training my mind. Through this course, I feel like I have gained a lot of useful knowledge. However, I am still striving to explore more. This course has shown me that there are many talented peers whom I need to look up to for further improvement in generating ideas and conducting research.
Professor Jong told us in class that grades are a tool. In my opinion, I have earned the highest grade, which will increase my GPA. I can use this tool for my future PhD application. My future goal is to dive into the world of science, which I love the most.
