scholarly journals Topoisomerase 1 dependent R-loop deficiency as a mechanism underlying oncogene-induced replication stress and genomic instability

2020 ◽  
Author(s):  
Dan Sarni ◽  
Alon Shtrikman ◽  
Yifat S. Oren ◽  
Batsheva Kerem
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Genomic Instability ◽  
Cancer Progression ◽  
Replication Stress ◽  
Genome Integrity ◽  
Replication Rate ◽  
Topoisomerase 1 ◽  
Replicative Stress ◽  
Complex Process

AbstractDNA replication is a complex process that is tightly regulated to ensure faithful genome duplication, and its perturbation leads to DNA damage and genomic instability. Oncogene expression triggers replicative stress that can lead to genetic instability, driving cancer progression. Thus, revealing the molecular basis for oncogene-induced replication stress is important for understanding of oncogenesis. Here we show that the activation of mutated HRAS leads to a non-canonical replication stress characterized by accelerated replication rate, inducing DNA damage. Mutated HRAS increases topoisomerase 1 (TOP1) expression, which leads to reduced levels of RNA-DNA hybrids (R-loops), driving fork acceleration and damage formation. Restoration of the perturbed replication either by restoration of TOP1 levels or directly by mild replication inhibition results in a dramatic reduction in DNA damage. The findings highlight the importance of TOP1 equilibrium in the regulation of R-loop homeostasis to ensure faithful DNA replication and genome integrity that when dysregulated can be a mechanism of oncogene-induced DNA damage.

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.

scholarly journals Harnessing DNA Replication Stress for Novel Cancer Therapy

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 990 ◽  
Author(s):  
Huanbo Zhu ◽  
Umang Swami ◽  
Ranjan Preet ◽  
Jun Zhang
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Replicative Stress ◽  
Combination Treatments ◽  
Damage Repair ◽  
Target Dna ◽  
Dna Replication Stress ◽  
Exogenous Factors

DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.

scholarly journals Targeting DNA Replication Stress and DNA Double-Strand Break Repair for Optimizing SCLC Treatment

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1289 ◽  
Author(s):  
Xing Bian ◽  
Wenchu Lin
Keyword(s):  
Lung Cancer ◽  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Repair ◽  
Predictive Biomarkers ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Repair System ◽  
Damage Repair ◽  
Repair Pathways

Small cell lung cancer (SCLC), accounting for about 15% of all cases of lung cancer worldwide, is the most lethal form of lung cancer. Despite an initially high response rate of SCLC to standard treatment, almost all patients are invariably relapsed within one year. Effective therapeutic strategies are urgently needed to improve clinical outcomes. Replication stress is a hallmark of SCLC due to several intrinsic factors. As a consequence, constitutive activation of the replication stress response (RSR) pathway and DNA damage repair system is involved in counteracting this genotoxic stress. Therefore, therapeutic targeting of such RSR and DNA damage repair pathways will be likely to kill SCLC cells preferentially and may be exploited in improving chemotherapeutic efficiency through interfering with DNA replication to exert their functions. Here, we summarize potentially valuable targets involved in the RSR and DNA damage repair pathways, rationales for targeting them in SCLC treatment and ongoing clinical trials, as well as possible predictive biomarkers for patient selection in the management of SCLC.

scholarly journals Protective Mechanisms Against DNA Replication Stress in the Nervous System

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 730
Author(s):  
Clara Forrer Charlier ◽  
Rodrigo A. P. Martins
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Replication ◽  
Neurological Diseases ◽  
Replication Stress ◽  
Nervous System Development ◽  
Stress Generation ◽  
Genome Replication ◽  
Cns Development ◽  
Dna Replication Stress

The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

scholarly journals Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites

2019 ◽  
Vol 48 (4) ◽  
pp. 1886-1904 ◽  
Author(s):  
Jihane Basbous ◽  
Antoine Aze ◽  
Laurent Chaloin ◽  
Rana Lebdy ◽  
Dana Hodroj ◽  
...  
Keyword(s):  
Dna Replication ◽  
Solid Tumors ◽  
Cancer Progression ◽  
Degradation Products ◽  
Replication Stress ◽  
Cellular Transformation ◽  
Chromosomal Dna ◽  
Normal Tissues ◽  
Dna Replication Stress ◽  
Pyrimidine Degradation

Abstract Imbalance in the level of the pyrimidine degradation products dihydrouracil and dihydrothymine is associated with cellular transformation and cancer progression. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP), a zinc metalloenzyme that is upregulated in solid tumors but not in the corresponding normal tissues. How dihydropyrimidine metabolites affect cellular phenotypes remains elusive. Here we show that the accumulation of dihydropyrimidines induces the formation of DNA–protein crosslinks (DPCs) and causes DNA replication and transcriptional stress. We used Xenopus egg extracts to recapitulate DNA replication invitro. We found that dihydropyrimidines interfere directly with the replication of both plasmid and chromosomal DNA. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits human DHP activity. Cellular exposure to dihydromyricetin triggered DPCs-dependent DNA replication stress in cancer cells. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.

Abstract 3031: Replication stress and DNA damage promote genomic instability in near-tetraploid colorectal cancer cells

2015 ◽  
Author(s):  
Isabel Quintanilla ◽  
Darawalee Wangsa ◽  
Markus Brown ◽  
Amaia Ercilla ◽  
Greg Klus ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Damage ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Replication Stress ◽  
Colorectal Cancer Cells

scholarly journals DNA replication and spindle checkpoints cooperate during S phase to delay mitosis and preserve genome integrity

2014 ◽  
Vol 204 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Maria M. Magiera ◽  
Elisabeth Gueydon ◽  
Etienne Schwob
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Forks ◽  
Mitotic Entry ◽  
Transient Activation ◽  
Spindle Checkpoints ◽  
Spindle Assembly Checkpoints

Deoxyribonucleic acid (DNA) replication and chromosome segregation must occur in ordered sequence to maintain genome integrity during cell proliferation. Checkpoint mechanisms delay mitosis when DNA is damaged or upon replication stress, but little is known on the coupling of S and M phases in unperturbed conditions. To address this issue, we postponed replication onset in budding yeast so that DNA synthesis is still underway when cells should enter mitosis. This delayed mitotic entry and progression by transient activation of the S phase, G2/M, and spindle assembly checkpoints. Disabling both Mec1/ATR- and Mad2-dependent controls caused lethality in cells with deferred S phase, accompanied by Rad52 foci and chromosome missegregation. Thus, in contrast to acute replication stress that triggers a sustained Mec1/ATR response, multiple pathways cooperate to restrain mitosis transiently when replication forks progress unhindered. We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex.

Reducing MCM Loading Causes Chromosomal Aneuploidy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3349-3349
Author(s):  
Stephen J. Orr ◽  
Terry Gaymes ◽  
Rong Wang ◽  
Barbara Czepulkowski ◽  
Darius Ladon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
T Cells ◽  
Dna Replication ◽  
Genomic Instability ◽  
Chromosomal Abnormalities ◽  
S Phase ◽  
Human T Cells ◽  
Dna Damage Responses ◽  
Mcm Proteins

Abstract Normal DNA replication must be accurate and occur only once per cell cycle. Sites of DNA replication are specified by binding the origin recognition complex, that includes minichromosome maintenance (MCM) proteins. Paradoxically, in higher eukaryotes MCM proteins are present in >20 fold excess of that required for DNA replication. They are also downregulated by elevated expression of proteins such as cyclin E that occurs in cancers, including AML and breast cancer. We investigated why human cells need “excess” MCM proteins and whether the reduction of MCM protein levels might contribute to a malignant phenotype. We determined the consequences of reducing the levels of MCM proteins in primary human T cells in which cell cycle controls and DNA damage responses are normal. Mass spectrometry sequencing of chromatin/nuclear matrix-bound proteins and western blotting identified that Mcm7 is not present in quiescent, normal primary human T cells. Mcm7 is induced in mid G1after the G0→G1 commitment point, the point beyond which T cells are committed to entering the cell cycle. Reduction of Mcm7 with siRNA to <5% of normal during G0→G1→S-phase reduces chromatin-binding of each of the MCM proteins that form the DNA helicase. However, these cells still enter S-phase and replicate DNA. Reducing MCM levels by titrating siRNA causes dose-dependent DNA-damage responses involving activation of ATR & ATM and Chk1 & Chk2. However, cells depleted of Mcm7 do not undergo apoptosis, rather reducing MCM levels even by 50% causes gross non-clonal chromosomal abnormalities normally found in genomic instability syndromes. M-FISH identified chromosome translocations, as well as loss and gain of individual chromosomes, which can occur individually or together in the same cell. Reducing MCM levels also causes misrepair by non-homologous end joining (NHEJ), and both NHEJ and homologous recombination (HR) are necessary for chromosomal abnormalities to occur. Therefore, “excess” MCM proteins that are present in a normal, proliferating cell are necessary for maintaining genome stability and reduction of MCM loading onto DNA that occurs in cancers is sufficient to cause genomic instability.

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