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DNA Repair

Jie Du, Narui Yin, Ting Xie, Yunfeng Zheng, Ning Xia, Jun Shang, Fei Chen, Haowen Zhang, Jiahua Yu, Fenju Liu
Homologous recombination (HR) and non-homologous end joining (NHEJ) are the two major mechanisms for the repair of DNA double-strand breaks (DSBs) in eukaryotic cells. Previously, we designed an assay for detecting NHEJ activity by using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, however, this approach cannot be used to predict the activity of HR repair. Hence, we developed a novel method that is capable of quantitatively measuring both HR and NHEJ activities via CRISPR/Cas9-induced oligodeoxynucleotide (ODN)-mediated DSB repair...
September 6, 2018: DNA Repair
Yi Zheng, Qijing Lei, Aldo Jongejan, Callista L Mulder, Saskia K M van Daalen, Sebastiaan Mastenbroek, Grace Hwang, Philip W Jordan, Sjoerd Repping, Geert Hamer
Lifelong mammalian male fertility is maintained through an intricate balance between spermatogonial proliferation and differentiation. DNA damage in spermatogonia, for instance caused by chemo- or radiotherapy, can induce cell cycle arrest or germ cell apoptosis, possibly resulting in male infertility. Spermatogonia are generally more radiosensitive and prone to undergo apoptosis than somatic cells. Among spermatogonial subtypes the response to DNA damage is differentially modulated; undifferentiated spermatogonia, including the spermatogonial stem cells (SSCs), are relatively radio-resistant, whereas differentiating spermatogonia are very radiosensitive...
August 28, 2018: DNA Repair
Torkild Visnes, Maurice Grube, Bishoy Magdy Fekry Hanna, Carlos Benitez-Buelga, Armando Cázares-Körner, Thomas Helleday
Base excision repair (BER) repairs mutagenic or genotoxic DNA base lesions, thought to be important for both the etiology and treatment of cancer. Cancer phenotypic stress induces oxidative lesions, and deamination products are responsible for one of the most prevalent mutational signatures in cancer. Chemotherapeutic agents induce genotoxic DNA base damage that are substrates for BER, while synthetic lethal approaches targeting BER-related factors are making their way into the clinic. Thus, there are three strategies by which BER is envisioned to be relevant in cancer chemotherapy: (i) to maintain cellular growth in the presence of endogenous DNA damage in stressed cancer cells, (ii) to maintain viability after exogenous DNA damage is introduced by therapeutic intervention, or (iii) to confer synthetic lethality in cancer cells that have lost one or more additional DNA repair pathways...
August 25, 2018: DNA Repair
Anissia Ait Saada, Sarah A E Lambert, Antony M Carr
Flaws in the DNA replication process have emerged as a leading driver of genome instability in human diseases. Alteration to replication fork progression is a defining feature of replication stress and the consequent failure to maintain fork integrity and complete genome duplication within a single round of S-phase compromises genetic integrity. This includes increased mutation rates, small and large scale genomic rearrangement and deleterious consequences for the subsequent mitosis that result in the transmission of additional DNA damage to the daughter cells...
August 25, 2018: DNA Repair
Boris P Belotserkovskii, Silvia Tornaletti, Alicia D D'Souza, Philip C Hanawalt
R-loops are structures consisting of an RNA-DNA duplex and an unpaired DNA strand. They can form during transcription upon nascent RNA "threadback" invasion into the DNA duplex to displace the non-template strand. Although R-loops occur naturally in all kingdoms of life and serve regulatory roles, they are often deleterious and can cause genomic instability. Of particular importance are the disastrous consequences when replication forks or transcription complexes collide with R-loops. The appropriate processing of R-loops is essential to avoid a number of human neurodegenerative and other clinical disorders...
August 25, 2018: DNA Repair
Charley C Gruber, Graham C Walker
Numerous lethal stresses in bacteria including antibiotics, thymineless death, and MalE-LacZ expression trigger an increase in the production of reactive oxygen species. This results in the oxidation of the nucleotide pool by radicals produced by Fenton chemistry. Following the incorporation of these oxidized nucleotides into the genome, the cell's unsuccessful attempt to repair these lesions through base excision repair (BER) contributes causally to the lethality of these stresses. We review the evidence for this phenomenon of incomplete BER-mediated cell death and discuss how better understanding this pathway could contribute to the development of new antibiotics...
August 25, 2018: DNA Repair
Michael J Howard, Samuel H Wilson
Site-specific DNA binding proteins must search the genome to locate their target sites, and many DNA modifying enzymes have the ability to scan along DNA in search of their substrates. This process is termed processive searching, and it serves to decrease the search time by effectively increasing the DNA binding footprint of a protein. The repertoire of proteins capable of processive searching is expanding, highlighting the need to understand the governing principles behind this fundamental process. Many of the enzymes in the base excision DNA repair pathway are capable of processive searching...
August 25, 2018: DNA Repair
David H Phillips
Reporter gene assays, in which a single mutation from each experiment can contribute to the assembly of a mutation spectrum for an agent, have provided the basis for understanding the mutational processes induced by mutagenic agents and for providing clues to the origins of mutations in human tumours. More recently exome and whole genome sequencing of human tumours has revealed distinct patterns of mutation that could provide additional clues for the causative origins of cancer. This can be tested by examining the mutational signatures induced in experimental systems by putative cancer-causing agents...
August 24, 2018: DNA Repair
Kyle T Powers, M Todd Washington
Normal DNA replication is blocked by DNA damage in the template strand. Translesion synthesis is a major pathway for overcoming these replication blocks. In this process, multiple non-classical DNA polymerases are thought to form a complex at the stalled replication fork that we refer to as the mutasome. This hypothetical multi-protein complex is structurally organized by the replication accessory factor PCNA and the non-classical polymerase Rev1. One of the non-classical polymerases within this complex then catalyzes replication through the damage...
August 24, 2018: DNA Repair
Erin E Kennedy, Paul J Caffrey, Sarah Delaney
The base excision repair (BER) pathway removes modified nucleobases that can be deleterious to an organism. BER is initiated by a glycosylase, which finds and removes these modified nucleobases. Most of the characterization of glycosylase activity has been conducted in the context of DNA oligomer substrates. However, DNA within eukaryotic organisms exists in a packaged environment with the basic unit of organization being the nucleosome core particle (NCP). The NCP is a complex substrate for repair in which a variety of factors can influence glycosylase activity...
August 24, 2018: DNA Repair
Marit E Geijer, Jurgen A Marteijn
Unperturbed transcription of eukaryotic genes by RNA polymerase II (Pol II) is crucial for proper cell function and tissue homeostasis. However, the DNA template of Pol II is continuously challenged by damaging agents that can result in transcription impediment. Stalling of Pol II on transcription-blocking lesions triggers a highly orchestrated cellular response to cope with these cytotoxic lesions. One of the first lines of defense is the transcription-coupled nucleotide excision repair (TC-NER) pathway that specifically removes transcription-blocking lesions thereby safeguarding unperturbed gene expression...
August 23, 2018: DNA Repair
J Brooks Crickard, Eric C Greene
Homologous recombination (HR) is a universally conserved mechanism used to maintain genomic integrity. In eukaryotes, HR is used to repair the spontaneous double strand breaks (DSBs) that arise during mitotic growth, and the programmed DSBs that form during meiosis. The mechanisms that govern mitotic and meiotic HR share many similarities, however, there are also several key differences, which reflect the unique attributes of each process. For instance, even though many of the proteins involved in mitotic and meiotic HR are the same, DNA target specificity is not: mitotic DSBs are repaired primarily using the sister chromatid as a template, whereas meiotic DBSs are repaired primarily through targeting of the homologous chromosome...
August 23, 2018: DNA Repair
Frederick W Alt, Bjoern Schwer
Early work from about two decades ago implicated DNA double-strand break (DSB) formation and repair in neuronal development. Findings emerging from recent studies of DSBs in proliferating neural progenitors and in mature, non-dividing neurons suggest important roles of DSBs in brain physiology, aging, cancer, psychiatric and neurodegenerative disorders. We provide an overview of some findings and speculate on what may lie ahead.
August 23, 2018: DNA Repair
Jinglin Lucy Xie, Daniel F Jarosz
From bacteria to humans, ancient stress responses enable organisms to contend with damage to both the genome and the proteome. These pathways have long been viewed as fundamentally separate responses. Yet recent discoveries from multiple fields have revealed surprising links between the two. Many DNA-damaging agents also target proteins, and mutagenesis induced by DNA damage produces variant proteins that are prone to misfolding, degradation, and aggregation. Likewise, recent studies have observed pervasive engagement of a p53-mediated response, and other factors linked to maintenance of genomic integrity, in response to misfolded protein stress...
August 23, 2018: DNA Repair
Atsushi Shibata, Penny Jeggo, Markus Löbrich
Canonical DNA non-homologous end-joining (c-NHEJ) and homologous recombination (HR), the two major DNA double-strand break (DSB) repair pathways, have long been depicted as competitors, fighting a race to rejoin DSBs. In human cells, Ku, an upstream component of NHEJ, is highly abundant and has exquisite end-binding capacity. Emerging evidence has suggested that Ku is the first protein binding most, if not all, DSBs, and creates a block to resection. Although most c-NHEJ proceeds without resection, recent studies have provided strong evidence for a process of resection-dependent c-NHEJ, that repairs a subset of DSBs...
August 23, 2018: DNA Repair
Alan D D'Andrea
BRCA1 and BRCA2 deficient tumor cells are sensitive to inhibitors of Poly ADP Ribose Polymerase (PARP1) through the mechanism of synthetic lethality. Several PARP inhibitors, which are oral drugs and generally well tolerated, have now received FDA approval for various ovarian cancer and breast cancer indications. Despite their use in the clinic, PARP inhibitor resistance is common and develops through multiple mechanisms. Broadly speaking, BRCA1/2-deficient tumor cells can become resistant to PARP inhibitors by restoring homologous recombination (HR) repair and/or by stabilizing their replication forks...
August 23, 2018: DNA Repair
Hiroshi Ide, Toshiaki Nakano, Amir M H Salem, Mahmoud I Shoulkamy
DNA is associated with proteins that are involved in its folding and transaction processes. When cells are exposed to chemical cross-linking agents or free radical-generating ionizing radiation, DNA-associated proteins are covalently trapped within the DNA to produce DNA-protein cross-links (DPCs). DPCs produced by these agents contain cross-linked proteins in an undisrupted DNA strand. Some DNA-metabolizing enzymes that form covalent reaction intermediates can also be irreversibly trapped in the presence of inhibitors or DNA damage to give rise to abortive DPCs...
August 23, 2018: DNA Repair
John M Pascal
Poly(ADP-ribose) polymerase (PARP) enzymes are broadly involved in the cellular response to DNA damage. PARP-1 is the chief human PARP enzyme involved in the DNA damage response, acting as a first responder that detects DNA strand breaks, and contributes to repair pathway choice and the efficiency of repair through modulation of chromatin structure and through interaction with and modification of a multitude of DNA repair factors. This perspective summarizes our knowledge of PARP-1 involvement in DNA repair pathways, and highlights recent structural and functional data regarding the activation of PARP-1 upon detecting DNA damage, and the release and trapping of PARP-1 at sites of DNA damage...
August 23, 2018: DNA Repair
Hong Mu, Nicholas E Geacintov, Suse Broyde, Jung-Eun Yeo, Orlando D Schärer
Global genome nucleotide excision repair (GG-NER) is the main pathway for the removal of bulky lesions from DNA and is characterized by an extraordinarily wide substrate specificity. Remarkably, the efficiency of lesion removal varies dramatically and certain lesions escape repair altogether and are therefore associated with high levels of mutagenicity. Central to the multistep mechanism of damage recognition in NER is the sensing of lesion-induced thermodynamic and structural alterations of DNA by the XPC-RAD23B protein and the verification of the damage by the transcription/repair factor TFIIH...
August 23, 2018: DNA Repair
Yaping Huang, Guo-Min Li
DNA mismatch repair (MMR) is an evolutionally conserved genome maintenance pathway and is well known for its role in maintaining replication fidelity by correcting biosynthetic errors generated during DNA replication. However, recent studies have shown that MMR preferentially protects actively transcribed genes from mutation during both DNA replication and transcription. This review describes the recent discoveries in this area. Potential mechanisms by which MMR safeguards actively transcribed genes are also discussed...
August 23, 2018: DNA Repair
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