scholarly journals How cancer cells hijack DNA double-strand break repair pathways to gain genomic instability

2015 ◽  
Vol 471 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Penny A. Jeggo ◽  
Markus Löbrich
Keyword(s):  
Cancer Cells ◽  
Genomic Instability ◽  
Mammalian Cells ◽  
Tumour Progression ◽  
Genetic Material ◽  
Strand Break ◽  
Cell Cycle Checkpoint ◽  
Dsb Repair ◽  
Normal Cells ◽  
Repair Pathways

DNA DSBs (double-strand breaks) are a significant threat to the viability of a normal cell, since they can result in loss of genetic material if mitosis or replication is attempted in their presence. Consequently, evolutionary pressure has resulted in multiple pathways and responses to enable DSBs to be repaired efficiently and faithfully. Cancer cells, which are under pressure to gain genomic instability, have a striking ability to avoid the elegant mechanisms by which normal cells maintain genomic stability. Current models suggest that, in normal cells, DSB repair occurs in a hierarchical manner that promotes rapid and efficient rejoining first, with the utilization of additional steps or pathways of diminished accuracy if rejoining is unsuccessful or delayed. In the present review, we evaluate the fidelity of DSB repair pathways and discuss how cancer cells promote the utilization of less accurate processes. Homologous recombination serves to promote accuracy and stability during replication, providing a battlefield for cancer to gain instability. Non-homologous end-joining, a major DSB repair pathway in mammalian cells, usually operates with high fidelity and only switches to less faithful modes if timely repair fails. The transition step is finely tuned and provides another point of attack during tumour progression. In addition to DSB repair, a DSB signalling response activates processes such as cell cycle checkpoint arrest, which enhance the possibility of accurate DSB repair. We consider the ways by which cancers modify and hijack these processes to gain genomic instability.

scholarly journals Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

2020 ◽  
Vol 21 (18) ◽  
pp. 6684
Author(s):  
Samuele Lodovichi ◽  
Tiziana Cervelli ◽  
Achille Pellicioli ◽  
Alvaro Galli
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Cancer Therapy ◽  
Clinical Outcome ◽  
Cancer Cells ◽  
Cell Cycle Checkpoint ◽  
Normal Cells ◽  
Cycle Checkpoint ◽  
Repair Pathways

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome.

Cell Lines and “Knock-in” Mice Bearing FLT3/ITD Mutations Exhibit Elevated Repair Errors Generated through Alternative DNA Double Strand Break Repair Pathways: Implications for Genomic Instability.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3237-3237
Author(s):  
Jinshui Fan ◽  
Li Li ◽  
Donald Small ◽  
Feyruz V. Rassool
Keyword(s):  
Genomic Instability ◽  
Cancer Progression ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Strand Break ◽  
Dna Ligase ◽  
Dsb Repair ◽  
Nhej Pathway ◽  
Primary Mouse

Abstract Abstract 3237 Poster Board III-174 Activating mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor occur in approximately 30% of acute myeloid leukemia (AML) patients and, at least for internal tandem duplication (ITD) mutations, are associated with poor prognosis. We previously reported that FLT3/ITD mutations are associated with increased reactive oxygen species (ROS) production which leads to increased DNA double strand breaks (DSBs) and decreased repair fidelity, that may in part explain aggressive AML in FLT3/ITD patients. While the DNA-PK and Ku-dependent non homologous end-joining (NHEJ) pathway is one of the main routes for repairing DSBs in normal mammalian cells, recent reports have suggested that an alternative and less well defined NHEJ pathway (Alt NHEJ) involving DNA ligase IIIαa and PARP1, characterized by DNA sequence microhomology at the repair junctions, may play a role in the generation of deletions and translocations that can lead to cancer progression. Here, we report that in hematopoetic progenitor cells expressing FLT3/ITD (Ba/F3/ITD), the frequency of errors and the size of deletions during DSB repair is increased compared with the Ba/F3 control cells. Moreover, these data are confirmed in bone marrow mononuclear cells (BM MNCs) from FLT3/ITD “knock-in” mice, compared with WT control cells. Strikingly, we show that Ku proteins (Ku70 and Ku86), key components of the main NHEJ pathway, are down-regulated in FLT3/ITD-positive cell line and primary mouse BM MNCs. Concomitantly, DNA ligase IIIαa, a component of Alt NHEJ pathway is up-regulated in FLT3/ITD-expressing cells and plays a role in abnormal DSB repair. Importantly, after treatment with a FLT3 inhibitor, AML (MOLM-14, MV4-11) cells containing FLT3/ITD mutations demonstrate a reduction of misrepair and deletion size, and down-regulation of DNA ligase IIIαa, suggesting that FLT3 signaling regulates the pathways by which DSBs are repaired. Thus, therapy to inhibit FLT3/ITD may lead to repair that reduces repair errors and genomic instability. Disclosures No relevant conflicts of interest to declare.

Shelterin-Mediated Telomere Protection

2018 ◽  
Vol 52 (1) ◽  
pp. 223-247 ◽  
Author(s):  
Titia de Lange
Keyword(s):  
Dna Damage ◽  
Ataxia Telangiectasia ◽  
Mammalian Cells ◽  
Current Knowledge ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
Homology Directed Repair ◽  
Telomere Protection ◽  
Repair Pathways

For more than a decade, it has been known that mammalian cells use shelterin to protect chromosome ends. Much progress has been made on the mechanism by which shelterin prevents telomeres from inadvertently activating DNA damage signaling and double-strand break (DSB) repair pathways. Shelterin averts activation of three DNA damage response enzymes [the ataxia-telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases and poly(ADP-ribose) polymerase 1 (PARP1)], blocks three DSB repair pathways [classical nonhomologous end joining (c-NHEJ), alternative (alt)-NHEJ, and homology-directed repair (HDR)], and prevents hyper-resection at telomeres. For several of these functions, mechanistic insights have emerged. In addition, much has been learned about how shelterin maintains the telomeric 3′ overhang, forms and protects the t-loop structure, and promotes replication through telomeres. These studies revealed that shelterin is compartmentalized, with individual subunits dedicated to distinct aspects of the end-protection problem. This review focuses on the current knowledge of shelterin-mediated telomere protection, highlights differences between human and mouse shelterin, and discusses some of the questions that remain.

Arabidopsis DNA double-strand break repair pathways

2004 ◽  
Vol 32 (6) ◽  
pp. 964-966 ◽  
Author(s):  
C.E. West ◽  
W.M. Waterworth ◽  
P.A. Sunderland ◽  
C.M. Bray
Keyword(s):  
Dna Damage ◽  
Genetic Material ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Dna Double Strand Break ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Transcript Profiles

DSBs (double-strand breaks) are one of the most serious forms of DNA damage that can occur in a cell's genome. DNA replication in cells containing DSBs, or following incorrect repair, may result in the loss of large amounts of genetic material, aneuploid daughter cells and cell death. There are two major pathways for DSB repair: HR (homologous recombination) uses an intact copy of the damaged region as a template for repair, whereas NHEJ (non-homologous end-joining) rejoins DNA ends independently of DNA sequence. In most plants, NHEJ is the predominant DSB repair pathway. Previously, the Arabidopsis NHEJ mutant atku80 was isolated and found to display hypersensitivity to bleomycin, a drug that causes DSBs in DNA. In the present study, the transcript profiles of wild-type and atku80 mutant plants grown in the presence and absence of bleomycin are determined by microarray analysis. Several genes displayed very strong transcriptional induction specifically in response to DNA damage, including the characterized DSB repair genes AtRAD51 and AtBRCA1. These results identify novel candidate genes that encode components of the DSB repair pathways active in NHEJ mutant plants.

scholarly journals Regulatory and Functional Involvement of Long Non-Coding RNAs in DNA Double-Strand Break Repair Mechanisms

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1506
Author(s):  
Angelos Papaspyropoulos ◽  
Nefeli Lagopati ◽  
Ioanna Mourkioti ◽  
Andriani Angelopoulou ◽  
Spyridon Kyriazis ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Strand Break ◽  
Dna Double Strand Breaks ◽  
End Joining ◽  
Dsb Repair ◽  
Repair Mechanisms ◽  
Non Coding Rnas ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Living Organisms

Protection of genome integrity is vital for all living organisms, particularly when DNA double-strand breaks (DSBs) occur. Eukaryotes have developed two main pathways, namely Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR), to repair DSBs. While most of the current research is focused on the role of key protein players in the functional regulation of DSB repair pathways, accumulating evidence has uncovered a novel class of regulating factors termed non-coding RNAs. Non-coding RNAs have been found to hold a pivotal role in the activation of DSB repair mechanisms, thereby safeguarding genomic stability. In particular, long non-coding RNAs (lncRNAs) have begun to emerge as new players with vast therapeutic potential. This review summarizes important advances in the field of lncRNAs, including characterization of recently identified lncRNAs, and their implication in DSB repair pathways in the context of tumorigenesis.

scholarly journals Phosphorylation: The Molecular Switch of Double-Strand Break Repair

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
K. C. Summers ◽  
F. Shen ◽  
E. A. Sierra Potchanant ◽  
E. A. Phipps ◽  
R. J. Hickey ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Genomic Stability ◽  
Molecular Switches ◽  
Strand Break ◽  
Nonhomologous End Joining ◽  
End Joining ◽  
Brca1 And Brca2 ◽  
Damage Response ◽  
Repair Mechanisms ◽  
Repair Pathways

Repair of double-stranded breaks (DSBs) is vital to maintaining genomic stability. In mammalian cells, DSBs are resolved in one of the following complex repair pathways: nonhomologous end-joining (NHEJ), homologous recombination (HR), or the inclusive DNA damage response (DDR). These repair pathways rely on factors that utilize reversible phosphorylation of proteins as molecular switches to regulate DNA repair. Many of these molecular switches overlap and play key roles in multiple pathways. For example, the NHEJ pathway and the DDR both utilize DNA-PK phosphorylation, whereas the HR pathway mediates repair with phosphorylation of RPA2, BRCA1, and BRCA2. Also, the DDR pathway utilizes the kinases ATM and ATR, as well as the phosphorylation of H2AX and MDC1. Together, these molecular switches regulate repair of DSBs by aiding in DSB recognition, pathway initiation, recruitment of repair factors, and the maintenance of repair mechanisms.

Double strand break (DSB) repair pathways in plants and their application in genome engineering

2021 ◽  
pp. 27-62
Author(s):  
Natalja Beying ◽  
◽  
Carla Schmidt ◽  
Holger Puchta ◽  
◽  
...  
Keyword(s):  
Genome Engineering ◽  
Plant Cells ◽  
Strand Break ◽  
End Joining ◽  
Dsb Repair ◽  
Strand Breaks ◽  
Repair Mechanisms ◽  
Repair Pathways ◽  
Non Homologous End Joining ◽  
Underlying Mechanisms

In genome engineering, after targeted induction of double strand breaks (DSBs) researchers take advantage of the organisms’ own repair mechanisms to induce different kinds of sequence changes into the genome. Therefore, understanding of the underlying mechanisms is essential. This chapter will review in detail the two main pathways of DSB repair in plant cells, non-homologous end joining (NHEJ) and homologous recombination (HR) and sum up what we have learned over the last decades about them. We summarize the different models that have been proposed and set these into relation with the molecular outcomes of different classes of DSB repair. Moreover, we describe the factors that have been identified to be involved in these pathways. Applying this knowledge of DSB repair should help us to improve the efficiency of different types of genome engineering in plants.

scholarly journals Defining the mutation signatures of DNA polymerase θ in cancer genomes

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Taejoo Hwang ◽  
Shelley Reh ◽  
Yerkin Dunbayev ◽  
Yi Zhong ◽  
Yoko Takata ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Dna Polymerase ◽  
Human Cancer ◽  
Strand Break ◽  
Base Substitution ◽  
Cancer Therapies ◽  
End Joining ◽  
Dsb Repair ◽  
Human Cancer Cells ◽  
Insertion And Deletion

Abstract DNA polymerase theta (POLQ)-mediated end joining (TMEJ) is a distinct pathway for mediating DNA double-strand break (DSB) repair. TMEJ is required for the viability of BRCA-mutated cancer cells. It is crucial to identify tumors that rely on POLQ activity for DSB repair, because such tumors are defective in other DSB repair pathways and have predicted sensitivity to POLQ inhibition and to cancer therapies that produce DSBs. We define here the POLQ-associated mutation signatures in human cancers, characterized by short insertions and deletions in a specific range of microhomologies. By analyzing 82 COSMIC (Catalogue of Somatic Mutations in Cancer) signatures, we found that BRCA-mutated cancers with a higher level of POLQ expression have a greatly enhanced representation of the small insertion and deletion signature 6, as well as single base substitution signature 3. Using human cancer cells with disruptions of POLQ, we further show that TMEJ dominates end joining of two separated DSBs (distal EJ). Templated insertions with microhomology are enriched in POLQ-dependent distal EJ. The use of this signature analysis will aid in identifying tumors relying on POLQ activity.

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