Post-translational modifications of lysine in DNA-damage repair

DNA damage in cells is often the result of constant genotoxic insult. Nevertheless, efficient DNA repair pathways are able to maintain genomic integrity. Over the past decade it has been revealed that it is not only kinase signalling pathways which play a central role in this process, but also the different post-translational modifications at lysine residues of histone (chromatin) and non-histone proteins. These lysine modifications include acetylation, methylation, ubiquitination and SUMOylation. Genomic instability is often the major cause of different diseases, especially cancer, where lysine modifications are altered and thereby have an impact on the various DNA repair mechanisms. This chapter will discuss the recent advances in our understanding of the role of different lysine modifications in DNA repair and its physiological consequences.

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DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13030504 ◽

2021 ◽

Vol 13 (3) ◽

pp. 504

Author(s):

Takayuki Saitoh ◽

Tsukasa Oda

Keyword(s):

Multiple Myeloma ◽

Dna Damage ◽

Dna Repair ◽

Tumor Microenvironment ◽

Dna Damage Response ◽

Genetic Instability ◽

Dna Repair Mechanisms ◽

Damage Response ◽

Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

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Ancient Sturgeons Possess Effective DNA Repair Mechanisms: Influence of Model Genotoxicants on Embryo Development of Sterlet, Acipenser ruthenus

International Journal of Molecular Sciences ◽

10.3390/ijms22010006 ◽

2020 ◽

Vol 22 (1) ◽

pp. 6

Author(s):

Ievgeniia Gazo ◽

Roman Franěk ◽

Radek Šindelka ◽

Ievgen Lebeda ◽

Sahana Shivaramu ◽

...

Keyword(s):

Gene Expression ◽

Dna Damage ◽

Dna Repair ◽

Embryo Development ◽

Hatching Rate ◽

Embryo Survival ◽

Dna Repair Mechanisms ◽

Acipenser Ruthenus ◽

Repair Mechanisms ◽

Sterlet Acipenser Ruthenus

DNA damage caused by exogenous or endogenous factors is a common challenge for developing fish embryos. DNA damage repair (DDR) pathways help organisms minimize adverse effects of DNA alterations. In terms of DNA repair mechanisms, sturgeons represent a particularly interesting model due to their exceptional genome plasticity. Sterlet (Acipenser ruthenus) is a relatively small species of sturgeon. The goal of this study was to assess the sensitivity of sterlet embryos to model genotoxicants (camptothecin, etoposide, and benzo[a]pyrene), and to assess DDR responses. We assessed the effects of genotoxicants on embryo survival, hatching rate, DNA fragmentation, gene expression, and phosphorylation of H2AX and ATM kinase. Exposure of sterlet embryos to 1 µM benzo[a]pyrene induced low levels of DNA damage accompanied by ATM phosphorylation and xpc gene expression. Conversely, 20 µM etoposide exposure induced DNA damage without activation of known DDR pathways. Effects of 10 nM camptothecin on embryo development were stage-specific, with early stages, before gastrulation, being most sensitive. Overall, this study provides foundational information for future investigation of sterlet DDR pathways.

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The emerging role of RNAs in DNA damage repair

Cell Death and Differentiation ◽

10.1038/cdd.2017.16 ◽

2017 ◽

Vol 24 (4) ◽

pp. 580-587 ◽

Cited By ~ 18

Author(s):

Ben R Hawley ◽

Wei-Ting Lu ◽

Ania Wilczynska ◽

Martin Bushell

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Critical Role ◽

Repair Process ◽

Rna Molecules ◽

Processing Enzymes ◽

Damage Repair ◽

New Findings ◽

Integral Role ◽

Repair Mechanisms

Abstract Many surveillance and repair mechanisms exist to maintain the integrity of our genome. All of the pathways described to date are controlled exclusively by proteins, which through their enzymatic activities identify breaks, propagate the damage signal, recruit further protein factors and ultimately resolve the break with little to no loss of genetic information. RNA is known to have an integral role in many cellular pathways, but, until very recently, was not considered to take part in the DNA repair process. Several reports demonstrated a conserved critical role for RNA-processing enzymes and RNA molecules in DNA repair, but the biogenesis of these damage-related RNAs and their mechanisms of action remain unknown. We will explore how these new findings challenge the idea of proteins being the sole participants in the response to DNA damage and reveal a new and exciting aspect of both DNA repair and RNA biology.

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽

10.1515/folmed-2017-0067 ◽

2018 ◽

Vol 60 (1) ◽

pp. 39-47 ◽

Cited By ~ 8

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel ◽

Dipen K. Sureja ◽

Kirtan P. Sanghavi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Repair Process ◽

Parp Inhibitors ◽

Brca Mutations ◽

Development Of Resistance ◽

Damage Repair ◽

Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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Aging and oxidative stress alter DNA repair mechanisms in male germ cells of superoxide dismutase-1 null mice

Biology of Reproduction ◽

10.1093/biolre/ioab114 ◽

2021 ◽

Author(s):

Paulina Nguyen-Powanda ◽

Bernard Robaire

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Dna Repair ◽

Superoxide Dismutase ◽

Germ Cells ◽

Superoxide Dismutase 1 ◽

Male Germ Cells ◽

Dna Repair Mechanisms ◽

Repair Mechanisms ◽

And Oxidative Stress

Abstract The efficiency of antioxidant defense system decreases with aging, thus resulting in high levels of reactive oxygen species (ROS) and DNA damage in spermatozoa. This damage can lead to genetic disorders in the offspring. There are limited studies investigating the effects of the total loss of antioxidants, such as superoxide dismutase-1 (SOD1), in male germ cells as they progress through spermatogenesis. In this study, we evaluated the effects of aging and removing SOD1 (in male germ cells of SOD1-null (Sod1−/−) mice) in order to determine the potential mechanism(s) of DNA damage in these cells. Immunohistochemical analysis showed an increase in lipid peroxidation and DNA damage in the germ cells of aged wild-type (WT) and Sod1−/− mice of all age. Immunostaining of OGG1, a marker of base excision repair (BER), increased in aged WT and young Sod1−/− mice. In contrast, immunostaining intensity of LIGIV and RAD51, markers of non-homologous end-joining (NHEJ) and homologous recombination (HR), respectively, decreased in aged and Sod1−/− mice. Gene expression analysis showed similar results with altered mRNA expression of these key DNA repair transcripts in pachytene spermatocytes and round spermatids of aged and Sod1−/− mice. Our study indicates that DNA repair pathway markers of BER, NHEJ, and HR are differentially regulated as a function of aging and oxidative stress in spermatocytes and spermatids, and aging enhances the repair response to increased oxidative DNA damage, whereas impairments in other DNA repair mechanisms may contribute to the increase in DNA damage caused by aging and the loss of SOD1.

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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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53BP1: function and mechanisms of focal recruitment

Biochemical Society Transactions ◽

10.1042/bst0370897 ◽

2009 ◽

Vol 37 (4) ◽

pp. 897-904 ◽

Cited By ~ 92

Author(s):

Jennifer E. FitzGerald ◽

Muriel Grenon ◽

Noel F. Lowndes

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Dna Damage Response ◽

Dna Damage Checkpoint ◽

Checkpoint Activation ◽

Damage Response ◽

Nuclear Structures ◽

Genotoxic Insult ◽

Covalent Histone Modifications

53BP1 (p53-binding protein 1) is classified as a mediator/adaptor of the DNA-damage response, and is recruited to nuclear structures termed foci following genotoxic insult. In the present paper, we review the functions of 53BP1 in DNA-damage checkpoint activation and DNA repair, and the mechanisms of its recruitment and activation following DNA damage. We focus in particular on the role of covalent histone modifications in this process.

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DNA repair mechanisms and gametogenesis

Reproduction ◽

10.1530/rep.0.1210031 ◽

2001 ◽

pp. 31-39 ◽

Cited By ~ 105

Author(s):

WM Baarends ◽

R van der Laan ◽

JA Grootegoed

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Gene Knockout ◽

Cell Cycle Checkpoint ◽

Checkpoint Control ◽

Chromatin Dynamics ◽

Dna Mismatch ◽

Dna Repair Mechanisms ◽

Genes Encoding ◽

Repair Mechanisms

In mammals, there is a complex and intriguing relationship between DNA repair and gametogenesis. DNA repair mechanisms are involved not only in the repair of different types of DNA damage in developing germline cells, but also take part in the meiotic recombination process. Furthermore, the DNA repair mechanisms should tolerate mutations occurring during gametogenesis, to a limited extent. In the present review, several gametogenic aspects of DNA mismatch repair, homologous recombination repair and postreplication repair are discussed. In addition, the role of DNA damage-induced cell cycle checkpoint control is considered briefly. It appears that many genes encoding proteins that take part in DNA repair mechanisms show enhanced or specialized expression during mammalian gametogenesis, and several gene knockout mouse models show male or female infertility. On the basis of such knowledge and models, future experiments may provide more information about the precise relationship between DNA repair, chromatin dynamics, and genomic stability versus instability during gametogenesis.

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