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DNA Repair

Amrita Sengupta, Devyani Haldar
Human sirtuin 3 (SIRT3) is a conserved NAD(+) dependent deacetylase, which functions in important cellular processes including transcription, metabolism, oxidative stress response. It is a robust mitochondrial deacetylase; however, few studies have indicated its nuclear functions. Here we report interaction of SIRT3 with core histones and identified acetylated histone H3 lysine 56 (H3K56ac) as its novel substrate, in addition to known substrates acetylated H4K16 and H3K9. Further, we showed in response to DNA damage SIRT3 localizes to the repair foci colocalizing with γH2AX and nonhomologous end joining (NHEJ) marker p53-binding protein 1 (53BP1)...
November 8, 2017: DNA Repair
Brett A Kaufman, Bennett Van Houten
The mitochondrial genome is a matrilineally inherited DNA that encodes numerous essential subunits of the respiratory chain in all metazoans. As such mitochondrial DNA (mtDNA) sequence integrity is vital to organismal survival, but it has a limited cadre of DNA repair activities, primarily base excision repair (BER). We have known that the mtDNA is significantly oxidized by both endogenous and exogenous sources, but this does not lead to the expected preferential formation of transversion mutations, which suggest a robust base excision repair (BER) system...
November 6, 2017: DNA Repair
Alexey N Evdokimov, Alexandra Yu Tsidulko, Alexander V Popov, Yury N Vorobiev, Alexander A Lomzov, Lyudmila S Koroleva, Vladimir N Silnikov, Irina O Petruseva, Olga I Lavrik
Mammalian nucleotide excision repair (NER) eliminates the broadest diversity of bulky lesions from DNA with wide specificity. However, the double incision efficiency for structurally different adducts can vary over several orders of magnitude. Therefore, great attention is drawn to the question of the relationship among structural properties of bulky DNA lesions and the rate of damage elimination. This paper studies the properties of several structurally diverse synthetic (model) DNAs containing bulky modifications...
November 2, 2017: DNA Repair
Rajendra Prasad, Melike Çağlayan, Da-Peng Dai, Cristina A Nadalutti, Ming-Lang Zhao, Natalie R Gassman, Agnes K Janoshazi, Donna F Stefanick, Julie K Horton, Rachel Krasich, Matthew J Longley, William C Copeland, Jack D Griffith, Samuel H Wilson
Mitochondrial genome integrity is fundamental to mammalian cell viability. Since mitochondrial DNA is constantly under attack from oxygen radicals released during ATP production, DNA repair is vital in removing oxidatively generated lesions in mitochondrial DNA, but the presence of a strong base excision repair system has not been demonstrated. Here, we addressed the presence of such a system in mammalian mitochondria involving the primary base lesion repair enzyme DNA polymerase (pol) β. Pol β was localized to mammalian mitochondria by electron microscopic-immunogold staining, immunofluorescence co-localization and biochemical experiments...
October 28, 2017: DNA Repair
Lihong Zhang, Yang Peng, Ivan P Uray, Jianfeng Shen, Lulu Wang, Xiangdong Peng, Powel H Brown, Wei Tu, Guang Peng
Investigation of natural products is an attractive strategy to identify novel compounds for cancer prevention and treatment. Numerous studies have shown the efficacy and safety of natural products, and they have been widely used as alternative treatments for a wide range of illnesses, including cancers. However, it remains unknown whether natural products affect homologous recombination (HR)-mediated DNA repair and whether these compounds can be used as sensitizers with minimal toxicity to improve patients' responses to radiation therapy, a mainstay of treatment for many human cancers...
October 24, 2017: DNA Repair
Michelle C Silva, Katie E Bryan, Milagros D Morrical, April M Averill, Julie Dragon, Adrian P Wiegmans, Scott W Morrical
The human RAD51 recombinase possesses DNA pairing and strand exchange activities that are essential for the error-free, homology-directed repair of DNA double-strand breaks. The recombination activities of RAD51 are activated upon its assembly into presynaptic filaments on single-stranded DNA at resected DSB ends. Defects in filament assembly caused by mutations in RAD51 or its regulators such as BRCA2 are associated with human cancer. Here we describe two novel RAD51 missense variants located in the multimerization/BRCA2 binding region of RAD51...
October 23, 2017: DNA Repair
Julie K Horton, Donna F Stefanick, Ming-Lang Zhao, Agnes K Janoshazi, Natalie R Gassman, Hannah J Seddon, Samuel H Wilson
Repair of DNA-protein crosslinks and oxidatively damaged DNA base lesions generates intermediates with nicks or gaps with abnormal and blocked 3'-phosphate and 5'-OH ends that prevent the activity of DNA polymerases and ligases. End cleaning in mammalian cells by Tdp1 and PNKP produces the conventional 3'-OH and 5'-phosphate DNA ends suitable for completion of repair. This repair function of PNKP is facilitated by its binding to the scaffold protein XRCC1, and phosphorylation of XRCC1 by CK2 at several consensus sites enables PNKP binding and recruitment to DNA damage...
October 19, 2017: DNA Repair
Phillip R Musich, Zhengke Li, Steven M Shell, Yue Zou
No abstract text is available yet for this article.
October 18, 2017: DNA Repair
Jing Li, Matthew Summerlin, Karin C Nitiss, John L Nitiss, Leslyn A Hanakahi
Tyrosyl-DNA phosphodiesterase 1 (TDP1) can remove a wide variety of 3' and 5' terminal DNA adducts. Genetic studies in yeast identified TDP1 as a regulator of non-homologous end joining (NHEJ) fidelity in the repair of double-strand breaks (DSBs) lacking terminal adducts. In this communication, we show that TDP1 plays an important role in joining cohesive DSBs in human cells. To investigate the role of TDP1 in NHEJ in live human cells we used CRISPR/cas9 to produce TDP1-knockout (TDP1-KO) HEK-293 cells. As expected, human TDP1-KO cells were highly sensitive to topoisomerase poisons and ionizing radiation...
October 16, 2017: DNA Repair
Umesh Yadava, Sanjai Kumar Yadav, Ramesh Kumar Yadav
In this paper, computational investigations have been carried out on an aromatic bis-amidine which is considered to be crucial due to its peculiar properties including anti-Pneumocystis carinii pneumonia(PCP), anti-inflammatory and anticancer activities. The raw structure of an aromatic bis-amidine namely; 2,5-bis[4-(N-cyclohexyl-amidino)phenyl]furan was retrieved, optimized and geometrical parameters were computed. The computational results have been compared with those of reported experimental values. In order to check its binding capability, we pave the way a step further by the interaction of the molecule with DNA duplex, 5'(CGCGAATTCGCG)3', which consisted of A/T base pairs in its central region...
October 16, 2017: DNA Repair
Kristina M Chapman, Megan M Wilkey, Kendall E Potter, Barbara C Waldman, Alan S Waldman
We investigated the impact of sequence divergence on DNA double-strand break (DSB) repair occurring via recombination in cultured thymidine kinase deficient mouse fibroblasts. We stably transfected cells with a DNA construct harboring a herpes thymidine kinase (tk) gene (the "recipient") rendered nonfunctional by insertion of an oligonucleotide containing the recognition site for endonuclease I-SceI. The construct also contained a closely linked truncated "donor" tk sequence. The donor could potentially restore function to the recipient gene via recombination provoked by induction of a DSB at the I-SceI site in the recipient...
October 16, 2017: DNA Repair
Timothy R L Howes, Annahita Sallymr, Rhys Brooks, George E Greco, Darin E Jones, Yoshihiro Matsumoto, Alan E Tomkinson
In human cells, there are three genes that encode DNA ligase polypeptides with distinct but overlapping functions. Previously small molecule inhibitors of human DNA ligases were identified using a structure-based approach. Three of these inhibitors, L82, a DNA ligase I (LigI)-selective inhibitor, and L67, an inhibitor of LigI and DNA ligases III (LigIII), and L189, an inhibitor of all three human DNA ligases, have related structures that are composed of two 6-member aromatic rings separated by different linkers...
October 10, 2017: DNA Repair
Qiongyu Yan, Huiqin Zhu, Li Lan, Jing Yi, Jie Yang
Non-homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks (DSBs) requires the formation of a Ku70/Ku80/DNA-PKcs complex at the DSB sites. A previous study has revealed Ku80 cleavage by caspase-3 during apoptosis. However, it remains largely unknown whether and how Ku80 cleavage affects its function in mediating NHEJ-mediated DNA repair. Here we report that Ku80 can be cleaved by caspases-2 at D726 upon a transient etoposide treatment. Caspase-2-mediated Ku80 cleavage promotes Ku80/DNA-PKcs interaction as the D726A mutation diminished Ku80 interaction with DNA-PKcs, while a Ku80 truncate (Ku80 ΔC6) lacking all the 6 residues following D726 rescued the weakened Ku80/DNA-PKcs interaction caused by caspase-2 knockdown...
October 10, 2017: DNA Repair
Enni Markkanen
Oxidative DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the pathogenesis of a wide variety of diseases, including cancer and neurodegeneration. 7,8-dihydro-8oxo-deoxyGuanine (8-oxo-G) is one of the best characterised oxidative DNA lesions, and it can give rise to point mutations due to its miscoding potential that instructs most DNA polymerases (Pols) to preferentially insert Adenine (A) opposite 8-oxo-G instead of the correct Cytosine (C). If uncorrected, A:8-oxo-G mispairs can give rise to C:G→A:T transversion mutations...
September 22, 2017: DNA Repair
Marina Raguse, Rubén Torres, Elena M Seco, Carolina Gándara, Silvia Ayora, Ralf Moeller, Juan C Alonso
The mechanisms that allow to circumvent replicative stress, and to resume DNA synthesis are poorly understood in Bacillus subtilis. To study the role of the diadenylate cyclase DisA and branch migration translocase (BMT) RadA/Sms in restarting a stalled replication fork, we nicked and broke the circular chromosome of an inert mature haploid spore, damaged the bases, and measured survival of reviving spores. During undisturbed ripening, nicks and breaks should be repaired by pathways that do not invoke long-range end resection or genetic exchange by homologous recombination, after which DNA replication might be initiated...
September 22, 2017: DNA Repair
Roketa Sloan, Shar-Yin Naomi Huang, Yves Pommier, Sue Jinks-Robertson
Topoisomerase I (Top1) removes DNA torsional stress by nicking and resealing one strand of DNA, and is essential in higher eukaryotes. The enzyme is frequently overproduced in tumors and is the sole target of the chemotherapeutic drug camptothecin (CPT) and its clinical derivatives. CPT stabilizes the covalent Top1-DNA cleavage intermediate, which leads to toxic double-strand breaks (DSBs) when encountered by a replication fork. In the current study, we examined genetic instability associated with CPT treatment or with Top1 overexpression in the yeast Saccharomyces cerevisiae...
September 18, 2017: DNA Repair
Komal Pekhale, Gauri Haval, Nusrat Perween, Giulia Antoniali, Gianluca Tell, Surendra Ghaskadbi, Saroj Ghaskadbi
Only mammalian apurinic/apyrimidinic endonuclease1 (APE1) has been reported to possess both DNA repair and redox activities. C terminal of the protein is required for base excision repair, while the redox activity resides in the N terminal due to cysteine residues at specific positions. APE1s from other organisms studied so far lack the redox activity in spite of having the N terminal domain. We find that APE1 from the Cnidarian Hydra exhibits both endonuclease and redox activities similar to mammalian APE1...
September 18, 2017: DNA Repair
Ingrid R Alves, Marco A Lima-Noronha, Larissa G Silva, Frank S Fernández-Silva, Aline Luiza D Freitas, Marilis V Marques, Rodrigo S Galhardo
imuABC (imuAB dnaE2) genes are responsible for SOS-mutagenesis in Caulobacter crescentus and other bacterial species devoid of umuDC. In this work, we have constructed operator-constitutive mutants of the imuABC operon. We used this genetic tool to investigate the effect of SOS-induced levels of these genes upon both spontaneous and damage-induced mutagenesis. We showed that constitutive expression of imuABC does not increase spontaneous or damage-induced mutagenesis, nor increases cellular resistance to DNA-damaging agents...
September 14, 2017: DNA Repair
Diana Azenha, Maria Celeste Lopes, Teresa C Martins
Cancer remains one of the leading causes of mortality worldwide. Most cancers present high degrees of genomic instability. DNA damage and replication checkpoints function as barriers to halt cell cycle progression until damage is resolved, preventing the perpetuation of errors. Activation of these checkpoints is critically dependent on Claspin, an adaptor protein that mediates the phosphorylation of the effector kinase Chk1 by ATR. However, Claspin also performs other roles related to the protection and maintenance of cell and genome integrity...
September 8, 2017: DNA Repair
Pan-Pan Jia, Muhammad Junaid, Yan-Bo Ma, Farooq Ahmad, Yong-Fang Jia, Wei-Guo Li, De-Sheng Pei
DNA nuclease/helicase 2 (DNA2), a multi-functional protein protecting the high fidelity of genomic transmission, plays critical roles in DNA replication and repair processes. In the maturation of Okazaki fragments, DNA2 acts synergistically with other enzymes to cleave the DNA-RNA primer flaps via different pathways. DNA2 is also involved in the stability of mitochondrial DNA and the maintenance of telomeres. Moreover, DNA2 potentially participates in controlling the cell cycle by repairing the DNA replication faults at main checkpoints...
September 6, 2017: DNA Repair
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