DNA Damage and Genomic Instability Induced by Inappropriate DNA Re-replication

2007 ◽  
Author(s):  
Brian M. Green ◽  
Joachim J. Li
Keyword(s):  
Dna Damage ◽  
Genomic Instability

scholarly journals Eukaryotic clamp loaders and unloaders in the maintenance of genome stability

2020 ◽  
Vol 52 (12) ◽  
pp. 1948-1958
Author(s):  
Kyoo-young Lee ◽  
Su Hyung Park
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Genome Stability ◽  
Critical Role ◽  
Nuclear Antigen ◽  
Checkpoint Activation ◽  
Sliding Clamp ◽  
Clamp Loaders ◽  
Factor C

AbstractEukaryotic sliding clamp proliferating cell nuclear antigen (PCNA) plays a critical role as a processivity factor for DNA polymerases and as a binding and acting platform for many proteins. The ring-shaped PCNA homotrimer and the DNA damage checkpoint clamp 9-1-1 are loaded onto DNA by clamp loaders. PCNA can be loaded by the pentameric replication factor C (RFC) complex and the CTF18-RFC-like complex (RLC) in vitro. In cells, each complex loads PCNA for different purposes; RFC-loaded PCNA is essential for DNA replication, while CTF18-RLC-loaded PCNA participates in cohesion establishment and checkpoint activation. After completing its tasks, PCNA is unloaded by ATAD5 (Elg1 in yeast)-RLC. The 9-1-1 clamp is loaded at DNA damage sites by RAD17 (Rad24 in yeast)-RLC. All five RFC complex components, but none of the three large subunits of RLC, CTF18, ATAD5, or RAD17, are essential for cell survival; however, deficiency of the three RLC proteins leads to genomic instability. In this review, we describe recent findings that contribute to the understanding of the basic roles of the RFC complex and RLCs and how genomic instability due to deficiency of the three RLCs is linked to the molecular and cellular activity of RLC, particularly focusing on ATAD5 (Elg1).

scholarly journals Germ granule dysfunction is a hallmark and mirror of Piwi mutant sterility

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maya Spichal ◽  
Bree Heestand ◽  
Katherine Kretovich Billmyre ◽  
Stephen Frenk ◽  
Craig C. Mello ◽  
...  
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Environmental Restoration ◽  
Related Gene ◽  
C Elegans ◽  
Dna Damage Signaling ◽  
Multiple Phenotypes ◽  
Granule Structure ◽  
Germ Granules ◽  
Late Generation

AbstractIn several species, Piwi/piRNA genome silencing defects cause immediate sterility that correlates with transposon expression and transposon-induced genomic instability. In C. elegans, mutations in the Piwi-related gene (prg-1) and other piRNA deficient mutants cause a transgenerational decline in fertility over a period of several generations. Here we show that the sterility of late generation piRNA mutants correlates poorly with increases in DNA damage signaling. Instead, sterile individuals consistently exhibit altered perinuclear germ granules. We show that disruption of germ granules does not activate transposon expression but induces multiple phenotypes found in sterile prg-1 pathway mutants. Furthermore, loss of the germ granule component pgl-1 enhances prg-1 mutant infertility. Environmental restoration of germ granule function for sterile pgl-1 mutants restores their fertility. We propose that Piwi mutant sterility is a reproductive arrest phenotype that is characterized by perturbed germ granule structure and is phenocopied by germ granule dysfunction, independent of genomic instability.

scholarly journals Obesity, oxidative DNA damage and vitamin D as predictors of genomic instability in children and adolescents

2021 ◽  
Author(s):  
Moonisah Usman ◽  
Maria Woloshynowych ◽  
Jessica Carrilho Britto ◽  
Ivona Bilkevic ◽  
Bethany Glassar ◽  
...  
Keyword(s):  
Vitamin D ◽  
Dna Damage ◽  
Genomic Instability ◽  
Oxidative Dna Damage ◽  
Nutritional Deficiencies ◽  
Aetiological Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Childhood And Adolescence ◽  
Paediatric Obesity ◽  
Vitamin D Levels

Abstract Background/objectives Epidemiological evidence indicates obesity in childhood and adolescence to be an independent risk factor for cancer and premature mortality in adulthood. Pathological implications from excess adiposity may begin early in life. Obesity is concurrent with a state of chronic inflammation, a well-known aetiological factor for DNA damage. In addition, obesity has been associated with micro-nutritional deficiencies. Vitamin D has attracted attention for its anti-inflammatory properties and role in genomic integrity and stability. The aim of this study was to determine a novel approach for predicting genomic instability via the combined assessment of adiposity, DNA damage, systemic inflammation, and vitamin D status. Subjects/methods We carried out a cross-sectional study with 132 participants, aged 10–18, recruited from schools and paediatric obesity clinics in London. Anthropometric assessments included BMI Z-score, waist and hip circumference, and body fat percentage via bioelectrical impedance. Inflammation and vitamin D levels in saliva were assessed by enzyme-linked immunosorbent assay. Oxidative DNA damage was determined via quantification of 8-hydroxy-2′-deoxyguanosine in urine. Exfoliated cells from the oral cavity were scored for genomic instability via the buccal cytome assay. Results As expected, comparisons between participants with obesity and normal range BMI showed significant differences in anthropometric measures (p < 0.001). Significant differences were also observed in some measures of genomic instability (p < 0.001). When examining relationships between variables for all participants, markers of adiposity positively correlated with acquired oxidative DNA damage (p < 0.01) and genomic instability (p < 0.001), and negatively correlated with vitamin D (p < 0.01). Multiple regression analyses identified obesity (p < 0.001), vitamin D (p < 0.001), and oxidative DNA damage (p < 0.05) as the three significant predictors of genomic instability. Conclusions Obesity, oxidative DNA damage, and vitamin D deficiency are significant predictors of genomic instability. Non-invasive biomonitoring and predictive modelling of genomic instability in young patients with obesity may contribute to the prioritisation and severity of clinical intervention measures.

scholarly journals Human papillomavirus E7 oncoprotein targets RNF168 to hijack the host DNA damage response

2019 ◽  
Vol 116 (39) ◽  
pp. 19552-19562 ◽  
Author(s):  
Justine Sitz ◽  
Sophie Anne Blanchet ◽  
Steven F. Gameiro ◽  
Elise Biquand ◽  
Tia M. Morgan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Genomic Instability ◽  
E3 Ligase ◽  
Human Papillomaviruses ◽  
Double Strand Breaks ◽  
Nuclear Bodies ◽  
Dna Double Strand Breaks ◽  
Strand Breaks

High-risk human papillomaviruses (HR-HPVs) promote cervical cancer as well as a subset of anogenital and head and neck cancers. Due to their limited coding capacity, HPVs hijack the host cell’s DNA replication and repair machineries to replicate their own genomes. How this host–pathogen interaction contributes to genomic instability is unknown. Here, we report that HPV-infected cancer cells express high levels of RNF168, an E3 ubiquitin ligase that is critical for proper DNA repair following DNA double-strand breaks, and accumulate high numbers of 53BP1 nuclear bodies, a marker of genomic instability induced by replication stress. We describe a mechanism by which HPV E7 subverts the function of RNF168 at DNA double-strand breaks, providing a rationale for increased homology-directed recombination in E6/E7-expressing cervical cancer cells. By targeting a new regulatory domain of RNF168, E7 binds directly to the E3 ligase without affecting its enzymatic activity. As RNF168 knockdown impairs viral genome amplification in differentiated keratinocytes, we propose that E7 hijacks the E3 ligase to promote the viral replicative cycle. This study reveals a mechanism by which tumor viruses reshape the cellular response to DNA damage by manipulating RNF168-dependent ubiquitin signaling. Importantly, our findings reveal a pathway by which HPV may promote the genomic instability that drives oncogenesis.

scholarly journals Checkpoint Adaptation Precedes Spontaneous and Damage-Induced Genomic Instability in Yeast

2001 ◽  
Vol 21 (5) ◽  
pp. 1710-1718 ◽  
Author(s):  
David J. Galgoczy ◽  
David P. Toczyski
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genomic Instability ◽  
Cell Cycle Progression ◽  
Repair Process ◽  
Yeast Cells ◽  
Chromosome Loss ◽  
Checkpoint Adaptation ◽  
Block Cell Cycle Progression ◽  
Break Induced Replication

ABSTRACT Despite the fact that eukaryotic cells enlist checkpoints to block cell cycle progression when their DNA is damaged, cells still undergo frequent genetic rearrangements, both spontaneously and in response to genotoxic agents. We and others have previously characterized a phenomenon (adaptation) in which yeast cells that are arrested at a DNA damage checkpoint eventually override this arrest and reenter the cell cycle, despite the fact that they have not repaired the DNA damage that elicited the arrest. Here, we use mutants that are defective in checkpoint adaptation to show that adaptation is important for achieving the highest possible viability after exposure to DNA-damaging agents, but it also acts as an entrée into some forms of genomic instability. Specifically, the spontaneous and X-ray-induced frequencies of chromosome loss, translocations, and a repair process called break-induced replication occur at significantly reduced rates in adaptation-defective mutants. This indicates that these events occur after a cell has first arrested at the checkpoint and then adapted to that arrest. Because malignant progression frequently involves loss of genes that function in DNA repair, adaptation may promote tumorigenesis by allowing genomic instability to occur in the absence of repair.

TREX1 is a checkpoint for innate immune sensing of DNA damage that fosters cancer immune resistance

2017 ◽  
Vol 1 (5) ◽  
pp. 509-515
Author(s):  
Sandra Demaria ◽  
Claire Vanpouille-Box
Keyword(s):  
Dna Damage ◽  
Immune Responses ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Cancer Progression ◽  
Type I ◽  
Replicative Stress ◽  
Immune Resistance ◽  
Cytoplasmic Dna ◽  
Autoimmune Pathology

Genomic instability is a hallmark of neoplastic transformation that leads to the accumulation of mutations, and generates a state of replicative stress in neoplastic cells associated with dysregulated DNA damage repair (DDR) responses. The importance of increasing mutations in driving cancer progression is well established, whereas relatively little attention has been devoted to the DNA displaced to the cytosol of cancer cells, a byproduct of genomic instability and of the ensuing DDR response. The presence of DNA in the cytosol promotes the activation of viral defense pathways in all cells, leading to activation of innate and adaptive immune responses. In fact, the improper accumulation of cytosolic DNA in normal cells is known to drive severe autoimmune pathology. Thus, cancer cells must evade cytoplasmic DNA detection pathways to avoid immune-mediated destruction. The main sensor for cytoplasmic DNA is the cyclic GMP–AMP synthase, cGAS. Upon activation by cytosolic DNA, cGAS catalyzes the formation of the second messenger cGAMP, which activates STING (stimulator of IFN genes), leading to the production of type I interferon (IFN-I). IFN-I is a critical effector of cell-mediated antiviral and antitumor immunity, and its production by cancer cells can be subverted by several mechanisms. However, the key upstream regulator of cytosolic DNA-mediated immune stimulation is the DNA exonuclease 3′-repair exonuclease 1 (TREX1). Here, we will discuss evidence in support of a role of TREX1 as an immune checkpoint that, when up-regulated, hinders the development of antitumor immune responses.

Genomic profiling of biliary tract cancers to reveal clinically actionable genes and therapeutic biomarkers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16187-e16187
Author(s):  
Yang Shao ◽  
Qiuxiang Ou ◽  
Zhenhao Fang ◽  
Rui Liu ◽  
Hua Bao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Biliary Tract ◽  
Large Scale ◽  
Excision Repair ◽  
State Transitions ◽  
Pathway Enrichment Analysis ◽  
Distal Cholangiocarcinoma ◽  
Tract Cancer

e16187 Background: Bile tract cancers are genetically and clinically heterogenous with a poor prognosis. Identifying novel biomarkers for targeted therapy is required to improve the clinical outcome of bile tract cancer patients. Methods: Tumor tissue samples of 482 Chinese biliary tract cancer (BTC) patients were genetically profiled using targeted next generation sequencing. Tumor mutation burden (TMB) was calculated by counting all nonsynonymous mutations per megabase of coding sequences. The R package ReactomePA was used in pathway enrichment analysis. Genomic instability was characterized by an in-house developed NGS-based Homologous Recombination Deficiency (HRD) panel and a HRD score was an unweighted sum of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST) scores. Results: The BTC cohort consisted of 135 gallbladder cancer (GBC), 73 intrahepatic cholangiocarcinoma (iCCA), 18 distal cholangiocarcinoma (dCCA), 14 perihilar cholangiocarcinoma (pCCA), while the remaining 242 BTC patients of no specific subtype information. Most frequently mutated genes included TP53 (56%), KRAS (25%), ARID1A (17%), SMAD4 (11%), and CDKN2A (10%) . A preliminary pathway analysis revealed that mutations of DNA damage repair (DDR) pathway genes were enriched in the cohort ( p< 1e-10), accounting for over 70% of the patients, particularly in homologous recombination repair (HRR), Fanconi anemia (FA), mismatch repair (MMR), and base excision repair (BER) genes. More specifically, approximately 50% of the cohort carried at least one mutation of the HRR genes (43%) or MMR genes (14%). Patients with impaired MMR had increased microsatellite instability status (MSI) comparing to those with wildtype MMR (33% vs. 3.1%, p< 0.0001), and patients harboring HRR mutations demonstrated elevated genomic instability than those without such mutations (median HRD: 18 vs.14, p < 0.05), indicative of potential response to poly (ADP-ribose) polymerase (PARP) inhibitors and other DNA-damage agents. Furthermore, high TMB was found to be highly correlated with DDR gene alterations ( p =0.004). In addition, we observed higher mutation frequencies of BRCA1/2 genes (including somatic and germline) in GBCs in contrast to other BTC subtypes. Conclusions: We herein reported the genomic features of 482 Chinese BTC samples and highlighted the role of DDR pathways including HRR and MMR. These findings could be useful to establish treatment and diagnostic strategies for BTC patients based on genetic information.

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