Malfunction of the process of replication can lead to incorporation of wrong bases, which are mismatched with the complementary strand. To understand the role of dna repair activity in lung cancer, accurate, reproducible, and specific phenotype assays need to be developed and tested in. Induction of the survival response may allow interventions that improve health and extend the life span. Southern alberta cancer research institute, university of calgary, calgary, alberta, canada dna damage and dna repair spontaneous loss of bases alkylation of bases oxidation of bases uvlight induced damage. A link between aging and dna damage is illustrated by the accumulation of dna alterations seen in aging human and mouse cells, accelerated aging phenotypes progerias observed in patients with hereditary impairments in genome maintenance, and progressive failure of stem cell function and aging reminiscent tissue abnormalities observed in mouse. In human cells, both normal metabolic activities and environmental factors such as radiation can cause dna damage, resulting in as many as 1 million individual molecular lesions per cell per day.
Dna damage has emerged as a major culprit in cancer and many diseases related to aging. Jan vijg on dna damage, mutations and aging 1, part of a collection of online lectures. The endogenous background level of oxidantinduced dna damage in vivo has been assayed by measuring 8hydroxydeoxyguanosine oh8dg, thymine glycol and thymidine glycol in urine and oh8dg. The stability of the genome is supported by an intricate machinery of. Assays for measuring and quantifying dna damage nci.
Dna damage was also confirmed by detection of partial incorporation of 5ethynyl2deoxyuridine edu into the cell nuclei shown in figure 6b. Jul, 2009 this paper presents evidence that damage to nuclear dna ndna is a direct cause of aging in addition to the effects of ndna damage on cancer, apoptosis, and cellular senescence. In both cell lines, from exposure day 2, the amount of cells with pronounced dna damage and repair. Frontiers dna damage, repair, and cancer metabolism oncology. The first hypothesis about damage to dna as a possible primary cause of aging or a driver of aging, stems from the 1950s essentially.
However, what drives senescence in vivo is not clear. Dna damage can lead to mutations and toxicity, which contribute to cancer and premature aging. Importantly, the dnadamage response observed in aging and cancer. Dna damage, dna repair, aging, and neurodegeneration article pdf available in cold spring harbor perspectives in medicine 510 september 2015 with 1,574 reads how we measure reads. Nonreplicating cells do not generally generate mutations due to dna damage induced errors of replication. Dna repair is a collection of processes by which a cell identifies and corrects damage to the dna molecules that encode its genome. Jun 26, 2018 telomeres are small structures that protect the ends of your chromosomes.
Linking senescence with dna damage and the cell cycle. But no one fully understands the impact that telomere shortening has on our overall health. Molecular origins of cancer dna damage, aging, and. The dna containing a mutation still consists of a sequence of standard base pairs, and the altered dna sequence can be copied when the dna is replicated. Exposure to ionizing radiation or agents that induce dna doublestranded breaks dsbs, which is one of the most damaging types of lesions in dna, can result in damage to cells and or tissues. Well dive into the recent research surrounding telomere shortening, cancer, and aging. The dna damage theory of aging proposes that aging is a consequence of unrepaired accumulation of naturally occurring dna damages. Aging and agerelated diseases are caused in part by the accumulation of dna damage, which is probably due to declining dna repair capacity as well as ongoing dna damage induction 43, 79. Nuclear dna damage as a direct cause of aging rejuvenation. Dna damage is a major cause of senescence mandal et al. Unrepaired dna damage can give rise to genomic instability and induce signaling cas cades leading to cell senescence or cell death, which are cellular phenotypes associated with aging rodier et al. Dna damage, dna repair, aging, and neurodegeneration. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoin. Finally, the sasp also includes proteins that can help senescent cells evade immune recognition and clearance 92, 93.
Molecular origins of cancer dna damage, aging, and cancer. Chapter 16 dna damage, dna repair and cancer semantic. Indeed, the capacity to repair dna damage is thought to decline as cells age moriwaki et al. Bohr1,2 1department of cellular and molecular medicine, center for healthy aging, university of copenhagen. Association of oxidative dna damage and ber with cancer and aging. Rosinduced dna damage is believed to contribute to carcinogenesis, aging and neurodegeneration.
This approach may aid studies on modulation of cancer and aging. A mutation is a change in the dna sequence in which normal base pairs are substituted, added, deleted or rearranged. The endogenous background level of oxidantinduced dna damage in vivo has been assayed. But is nuclear dna damage and mutation a cause of aging.
Dna damage, dna repair, aging, and neurodegeneration ncbi. Dnadamageinduced type i interferon promotes senescence. Genome instability, defined as higher than normal rates of mutation, is a doubleedged sword. Skin aging reflects the accumulation of damage to dna from both internal and environmental sources. The role of shortening in cancer and aging, how to avo. No single molecular mechanism appears to account for. I mean originally, of course, the manhattan project was to develop a bomb, an atomic bomb. Given the frequency at which dna lesions occur approximately 104 per cell per day 1, a complex system of damage detection and repair is required in order to preserve the integrity of the genome. Dna damage is normally recognized and repaired by the intrinsic dna damage response machinery. Thus, accumulation of dna damage is a consequence of aging and not a leading cause. We asked the authors of the study what this could mean for your skin. The link between dna oxidative damage and cancer is evident from animal models lacking these dna repair and antioxidant proteins. Stem cell dna damage and genome mutation in the context of. To prevent photoaging and skin cancers, reduced exposure to dna damaging agent uvr and wellcontrolled dna repair mechanisms in escs are required to prevent photoaging and dna damage associated skin diseases, such as cutaneous basal cell and squamous cell carcinoma bccs and sccs.
Therefore, cancer and aging, both arising as the consequence of irreparable dna damage, can be considered as the two sides of the same coin. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. Abstract dna damage induces cellintrinsic checkpoints, including p53 and. If the damaged lesions are successfully repaired, the cells will survive. Mar 29, 2017 harvard scientists discovered a way to repair dna damage and reverse cellular aging. The endogenous background level of oxidantinduced dna damage in vivo has been assayed by measuring 8hydroxydeoxyguanosine oh8dg, thymine glycol and thymidine. Progress in identifying the important endogenous processes damaging dna and developing methods to assay this damage in individuals is presented.
Indeed, aging tissues show a steady accumulation of cells that harbor dna damage foci, similar to the foci that are found in senescent cells 29, 30, 144. New toolkit to repair dna breaks linked to aging, cancer and. Molecular epidemiology of oxidative damage to dna and cancer. Impairments in genome maintenance can result in the development of cancer as well as aging, as exemplified by a variety of cancer prone and accelerated aging syndromes that result from defects in dna repair pathways. Some people claim that telomere shortening is a major contributor to the aging process and development of disease. Our main finding is a positive association between age and dna damage in humans, both in males and females. Dna damage and senescence in osteoprogenitors expressing osx1.
Dna damage, dna repair, aging, and neurodegeneration scott maynard1, evandro fei fang 2, morten scheibyeknudsen, deborah l. Expression of dna repair genes may be reduced by inherited germ line mutations or genetic polymorphisms, or by epigenetic alterations or mutations in. Examples of accelerated aging syndromes associated with defects in dna repair mechanisms are contrasted. These nonreplicating cells do not commonly give rise to cancer, but they do accumulate dna damages with time that likely contribute to aging see dna damage theory of aging. Review article ultraviolet radiationinduced skin aging.
The more cells that suffer dna damage, the more likely it is that one or more cells experience exactly the type of damage needed to run amok as the selfreplicating seeds to a cancer. Although dna is not the only target changed with aging, taking account of the major role of this macromolecule in the regulation of all cellular structures and its own cell cycle, dna damage has been studied with particular attention. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant cancerous cells must acquire. Accumulating dna lesions in stem cells could be cytotoxic and or cytostatic leading to a large reduction in regenerative potential and homeostatic maintenance as observed in an ageing phenotype. Ionizing radiation can damage the dna genes in cells, which in turn may lead to cancer. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of polyadpribose polymerase inhibitors for treating brca12 mutated ovarian cancers. While solar uv induces the most frequent modifications of dna, air pollution and tobacco smoke. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. The aging organism responds to dna damage by cellautonomous and systemic ddr. Oxidative damage to dna may lead to mutations that activate oncogenes or inactivate tumor suppressor genes 32,121.
Secondly, we will examine how erroneous dna repair and persistent dna damage in stem and progenitor cells impact stem cells and tissues in the context of cancer initiation and aging. Here, we draw a picture integrating cell autonomous and noncellautonomous p53mediated ddrs with cancer prevention and lifespan regulation. Role of telomeres and telomerase in aging and cancer. Damage in this context is a dna alteration that has an abnormal structure. Dna has many elaborate mechanisms to repair any damage or distortion. In addition, dna damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and. Dna damage, dna repair and cancer carol bernstein, anil r. Taking into account these considerations, little doubt remains about the causative role of dna damage in tumorigenesis as well as in aging 17. Mutations arise either from inactivation of dna repair pathways or in a repaircompetent.
Sep 03, 2003 lung cancer is a logical disease for evaluating oxidative damage and the role of free radicals because the etiologic agents for lung cancer are tobacco carcinogens that are known to damage dna. And that also in turn driven by the manhattan project, where they realized the dangers, of course, of radiation. Dna damage or to telomeres that have become excessively short. The senescence pathway involves the formation of telomere dysfunction induced foci that contain dna damage response factors. So, aging in humans is accompanied by an increase in general dna damage. We have investigated genomewide expression patterns after uvinduced dna damage in cell culture and during aging in mice.
Here we used a genetic approach to determine if spontaneous nuclear dna damage is sufficient to initiate senescence in mammals. Harvard scientists discover how to repair dna damage. Dna damage responses and p53 in the aging process blood. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts dna damage. Although both mitochondrial and nuclear dna damage can contribute to aging, nuclear dna is the main subject of this analysis. Research paper induction of apoptosis and ferroptosis by a. For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. A dna damage can be a chemical addition or disruption to a base of dna creating an abnormal nucleotide or nucleotide fragment or a break in one or both chains of the dna strands.
In the absence of other changes, cells can remain in a quiescentsenescent state for years, which can be considered a tumor suppressor mechanism at least for longlived species such. Endogenous oxidative dna damage, aging, and cancer. On the other hand, genomic instability can have catastrophic consequences for agerelated diseases such as cancer. Nerrelated human diseases associated with cancer and aging. In dna damageinitiated aging, dna damage accumulates, along with dna repair deficiencies, resulting in genomic instability and accelerated cellular senescence. Cyclobutane dimers 6,4,photoproducts dna strand breaks. Dna damage is a change in the basic structure of dna that is not itself replicated when the dna is replicated. The incidence of cancer increases with age in humans and in laboratory animals alike. If dna damage accumulation exceeds the levels of repair systems or dna damage response is deficient, unrepaired damages would propagate in the cells. Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing dna damage. An introduction to aging science brought to you by the. The cometchip is a newly engineered platform for highthroughput analysis of dna damage in mammalian cells. Accumulation of senescent cells over time contributes to aging and agerelated diseases.
An examination of the importance of dna damage and the systems of genome maintenance in relation to aging is followed by an account of. To understand the outcome of p53 activity in cancer and aging it is crucial to understand how p53 mediates distinct outcomes of dna damage signaling in the context of cells and tissues. Dna damage checkpoints in stem cells, ageing and cancer nature. This system is termed the dna damage response ddr, and encompasses. When a few telomeres become critically shortened, there is a growth arrest state, at which time a dna damage signal and cellular senescence is normally triggered. Stem cells, dna damage, ageing and cancer sciencedirect. Aging is a major risk factor for neurodegeneration, cancer, and other chronic diseases hoeijmakers 2009. Na damage has emerged as a major culprit in cancer and many diseases related to aging. While solar uv induces the most frequent modifications of dna, air pollution and tobacco smoke have also been demonstrated to induce the cascade of repair responses triggered by dna damage.
Similar phenomenon was observed in a549 cells, with 73% of the cells with dsb and 62% with ssb. Mice deficient in repair of dna oxidative damage or reactive oxygen species ros detoxification typically are susceptible to cancer. Jun 05, 2014 to clarify this relation, we conducted a metaanalysis to investigate the association between age and dna damage in humans. Stimulation of p53 and its target gene p21 cip1 by the dna damage response ddr plays a fundamental role in the initiation of senescence by causing cell cycle arrest roninson, 2002. Pdf dna damage, dna repair, aging, and neurodegeneration. Although both mitochondrial and nuclear dna damage can contribute. Dna injury can induce mutations that cause cancer or cell death or senescence, contributing to aging. Examples of accelerated aging syndromes associated with defects in dna repair. Many dna repair pathways, as well as other cellular stress.
This webinar is brought to you by the scienceaaas custom publishing office. Germline aberrations in critical dna repair and dna damage response ddr genes cause cancer predisposition, whereas various tumors harbor somatic mutations causing defective ddr dna repair. The roles of dna damage and dna repair in cancer and aging. A direct damage reversal the direct reversal of dna damage is by far the simplest repair mechanism that involves a single polypeptide chain, with enzymatic properties which binds to the damage and restores the dna genome to its normal state in a singlereaction step. Dna damage checkpoints in stem cells, ageing and cancer.
Nuclear dna damage can contribute to aging either indirectly by. Both scientists and the beauty industry know that as we grow older, our cells accumulate dna damage while their ability to correctly repair it declines, leading to changes in appearance associated with aging. Endogenous oxidative dna damage, aging, and cancer taylor. It has long been known, but seemingly ignored by many, that alcohol is damaging, new studies from researchers at mrc laboratory of molecular biology and cancer research uk are explaining how alcohol damages dna in stem cells increasing the risks of developing cancer as published in nature. Base excision repair of oxidative dna damage and association. In addition, dna damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Although there has been a renewed interest in the field of cancer metabolism in the last decade, the link between metabolism and dna damage dna repair in cancer has yet to be appreciably explored. But even the highestenergy uv rays dont have enough energy to penetrate. Deficient dna repair due to a germ line mutation allows dna damages to increase, leading to increased frequencies of mutation, epimutation and cancer. Endogenous dna damage as a source of genomic instability in. The p53 gene is an important tumor suppressor and also an orchestrator of an extensive network of ddr factors that are relevant for adaptation to dna damage in the aging organism.
Many of these lesions cause structural damage to the dna molecule. Alcohol damages dna and increases cancer risks worldhealth. Natural cellular processes, exposure to radiation cosmic, medical e. Jan vijg on dna damage, mutations and aging 2, part of a collection of online lectures.
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