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translesion synthesis

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https://www.readbyqxmd.com/read/28924058/localization-of-cdc7-protein-kinase-during-dna-replication-in-saccharomyces-cerevisiae
#1
Daniel Rossbach, D Suzi Bryan, Jay R Hesselberth, Robert Sclafani
DDK, a conserved serine-threonine protein kinase composed of a regulatory subunit, Dbf4, and a catalytic subunit, Cdc7, is essential for DNA replication initiation during S phase of the cell cycle through MCM2-7 helicase phosphorylation. The biological significance of DDK is well characterized, but the full mechanism of how DDK associates with substrates remains unclear. Cdc7 is bound to chromatin in the Saccharomyces cerevisiae genome throughout the cell cycle, but there is little empirical evidence as to specific Cdc7 binding locations...
September 18, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28918480/sgs1-helicase-is-required-for-efficient-pcna-monoubiquitination-and-translesion-dna-synthesis-in-saccharomyces-cerevisiae
#2
Fangfang Li, Lindsay G Ball, Li Fan, Michelle Hanna, Wei Xiao
DNA-damage tolerance (DDT) is employed by eukaryotes to deal with replication blocks on the template strand, and is divided into two parallel pathways that are activated by sequential ubiquitination of proliferating cell nuclear antigen (PCNA) at the Lys164 residue. Rad6-Rad18-mediated PCNA monoubiquitination promotes translesion DNA synthesis (TLS) and the monoubiquitinated PCNA can be further polyubiquitinated by an Mms2-Ubc13-Rad5 complex, leading to error-free lesion bypass. We previously reported that the DNA helicase Sgs1 is required for error-free lesion bypass, probably through the double-Holliday junction migration and subsequent resolution...
September 16, 2017: Current Genetics
https://www.readbyqxmd.com/read/28887307/dynamic-feature-of-mitotic-arrest-deficient-2-like-protein-2-mad2l2-and-structural-basis-for-its-interaction-with-chromosome-alignment-maintaining-phosphoprotein-camp
#3
Kodai Hara, Shota Taharazako, Masanori Ikeda, Hiroki Fujita, Yoshiko Mikami, Sotaro Kikuchi, Asami Hishiki, Hideshi Yokoyama, Yoshinobu Ishikawa, Shin-Ichiro Kanno, Kozo Tanaka, Hiroshi Hashimoto
Mitotic arrest deficient 2-like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment-maintaining phosphoprotein (CAMP), a kinetochore-microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein-protein interactions (PPIs) that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2-CAMP interaction and the mitotic role of MAD2L2 remain unknown...
September 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28886337/replication-fork-slowing-and-reversal-upon-dna-damage-require-pcna-polyubiquitination-and-zranb3-dna-translocase-activity
#4
Marko Vujanovic, Jana Krietsch, Maria Chiara Raso, Nastassja Terraneo, Ralph Zellweger, Jonas A Schmid, Angelo Taglialatela, Jen-Wei Huang, Cory L Holland, Katharina Zwicky, Raquel Herrador, Heinz Jacobs, David Cortez, Alberto Ciccia, Lorenza Penengo, Massimo Lopes
DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance...
September 7, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28881136/coordination-and-substitution-of-dna-polymerases-in-response-to-genomic-obstacles
#5
Michael A Trakselis, Matthew T Cranford, Aurea M Chu
The ability for DNA polymerases (Pols) to overcome a variety of obstacles in its path to maintain genomic stability during replication is a complex endeavor. It requires the coordination of multiple Pols with differing specificities through molecular control and access to the replisome. Although a number of contacts directly between Pols and to accessory proteins have been identified forming the basis of a variety of holoenzyme (HE) complexes, the dynamics of Pol active site substitutions remain uncharacterized...
September 7, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28841374/translesion-dna-synthesis-in-cancer-molecular-mechanisms-and-therapeutic-opportunities
#6
Maroof K Zafar, Robert L Eoff
The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multi-faceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs...
August 25, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28841305/living-on-the-edge-dna-polymerase-lambda-between-genome-stability-and-mutagenesis
#7
Barbara van Loon, Ulrich Hubscher, Giovanni Maga
In human cells, only four DNA polymerases (pols) are necessary and sufficient for the duplication of the genetic information. However, more than a dozen DNA pols are required to maintain its integrity. Such a high degree of specialization, makes DNA repair pols able to cope with specific lesions or repair pathways. On the other hand, the same DNA pols can have partially overlapping roles, which could result in possible conflicts of functions, if the DNA pols are not properly regulated. DNA pol λ is a typical example of such an enzyme...
August 25, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28831681/neddylation-antagonizes-ubiquitination-of-proliferating-cell-nuclear-antigen-and-regulates-the-recruitment-of-polymerase-%C3%AE-in-response-to-oxidative-dna-damage
#8
Junhong Guan, Shuyu Yu, Xiaofeng Zheng
NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase η (polη) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination...
August 22, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28827409/genomic-and-functional-integrity-of-the-hematopoietic-system-requires-tolerance-of-oxidative-dna-lesions
#9
Ana Martín-Pardillos, Anastasia Tsaalbi-Shtylik, Si Chen, Seka Lazare, Ronald P van Os, Albertina Dethmers-Ausema, Nima Borhan Fakouri, Matthias Bosshard, Rossana Aprigliano, Barbara van Loon, Daniela C F Salvatori, Keiji Hashimoto, Celia Dingemanse-van der Spek, Masaaki Moriya, Lene Juel Rasmussen, Gerald de Haan, Marc H G P Raaijmakers, Niels de Wind
Endogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize ageing. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions, and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for Rev1, a core factor in DNA translesion synthesis (TLS), the post-replicative bypass of damaged nucleotides...
August 21, 2017: Blood
https://www.readbyqxmd.com/read/28817566/inhibition-of-mutagenic-translesion-synthesis-a-possible-strategy-for-improving-chemotherapy
#10
Kinrin Yamanaka, Nimrat Chatterjee, Michael T Hemann, Graham C Walker
No abstract text is available yet for this article.
August 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28810119/conformational-flexibility-of-the-benzyl-guanine-adduct-in-a-bypass-polymerase-active-site-permits-replication-insights-from-molecular-dynamics-simulations
#11
Katie A Wilson, Stacey D Wetmore
Although translesion synthesis (TLS) polymerases play key roles in replicating DNA that contains nucleobase addition products (adducts), there are many unknowns about their function. The present work gains indispensable structural insights from molecular dynamics simulations on the replication of O6-benzyl-guanine (Bz-dG) prior to bond formation during dCTP insertion opposite the adduct by Dpo4. When combined with previous X-ray crystal structures of the Bz-dG extension complex, molecular details are now available for each stage during a single TLS replication cycle for this carcinogenic lesion...
August 31, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28807928/role-of-translesion-synthesis-dna-polymerases-in-dna-replication-in-the-presence-of-a-weak-dna-polymerase-%C3%AE-in-saccharomyces-cerevisiae
#12
Likui Zhang, Yanchao Huang, Xinyuan Zhu, Yuxiao Wang, Haoqiang Shi, Min Chen, Kunming Dong, Xiaojian Zhou
Translesion synthesis (TLS) DNA polymerases (pols) are often mutagenic for lesion bypass due to their low fidelity. Here, we isolated a weak yeast DNA pol δ mutant that possessed amino acid substitution V592G by genetic selection. The pol3-V592G cells were sensitive to hydroxyurea (HU), which increases the requirement for dNTPs, and their HU sensitivity was suppressed by L612M substitution. We also demonstrated that V592G substitution suppressed the phosphonoacetic acid (PAA) sensitivity of pol3-L612M cells, suggesting a cycle of mutual suppression in the HU- and PAA-sensitive yeast DNA pol δ mutants as similarly observed in the optA1- and PAA-sensitive T4 DNA pol mutants...
August 14, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28806503/identification-of-the-dimer-exchange-interface-of-the-bacterial-dna-damage-response-protein-umud
#13
David A Murison, Rebecca C Timson, Bilyana N Koleva, Michael Ordazzo, Penny J Beuning
The Escherichia coli SOS response, an induced DNA damage response pathway, confers survival on bacterial cells by providing accurate repair mechanisms as well as the potentially mutagenic pathway translesion synthesis (TLS). The umuD gene products are upregulated after DNA damage and play roles in both nonmutagenic and mutagenic aspects of the SOS response. Full-length UmuD is expressed as a homodimer of 139-amino-acid subunits, which eventually cleaves its N-terminal 24 amino acids to form UmuD'. The cleavage product UmuD' and UmuC form the Y-family polymerase DNA Pol V (UmuD'2C) capable of performing TLS...
August 29, 2017: Biochemistry
https://www.readbyqxmd.com/read/28766157/transport-effects-on-multiple-component-reactions-in-optical-biosensors
#14
Ryan M Evans, David A Edwards
Optical biosensors are often used to measure kinetic rate constants associated with chemical reactions. Such instruments operate in the surface-volume configuration, in which ligand molecules are convected through a fluid-filled volume over a surface to which receptors are confined. Currently, scientists are using optical biosensors to measure the kinetic rate constants associated with DNA translesion synthesis-a process critical to DNA damage repair. Biosensor experiments to study this process involve multiple interacting components on the sensor surface...
August 1, 2017: Bulletin of Mathematical Biology
https://www.readbyqxmd.com/read/28761001/dna-damage-tolerance-in-hematopoietic-stem-and-progenitor-cells-in-mice
#15
Bas Pilzecker, Olimpia Alessandra Buoninfante, Paul van den Berk, Cesare Lancini, Ji-Ying Song, Elisabetta Citterio, Heinz Jacobs
DNA damage tolerance (DDT) enables bypassing of DNA lesions during replication, thereby preventing fork stalling, replication stress, and secondary DNA damage related to fork stalling. Three modes of DDT have been documented: translesion synthesis (TLS), template switching (TS), and repriming. TLS and TS depend on site-specific PCNA K164 monoubiquitination and polyubiquitination, respectively. To investigate the role of DDT in maintaining hematopoietic stem cells (HSCs) and progenitors, we used Pcna(K164R/K164R) mice as a unique DDT-defective mouse model...
August 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28752642/genome-wide-map-of-apn1-binding-sites-under-oxidative-stress-in-saccharomyces-cerevisiae
#16
Lydia P Morris, Andrew B Conley, Natalya Degtyareva, I King Jordan, Paul W Doetsch
The DNA is cells is continuously exposed to reactive oxygen species resulting in toxic and mutagenic DNA damage. Although the repair of oxidative DNA damage occurs primarily through the base excision repair (BER) pathway, the nucleotide excision repair (NER) pathway processes some of the same lesions. In addition, damage tolerance mechanisms, such as recombination and translesion synthesis, enable cells to tolerate oxidative DNA damage, especially when BER and NER capacities are exceeded. Thus, disruption of BER alone or disruption of BER and NER in Saccharomyces cerevisiae leads to increased mutations as well as large-scale genomic rearrangements...
July 27, 2017: Yeast
https://www.readbyqxmd.com/read/28724765/translesion-polymerase-pol-%C3%AE-is-required-for-efficient-epstein-barr-virus-infectivity-and-is-regulated-by-the-viral-deubiquitinating-enzyme-bplf1
#17
Ossie F Dyson, Joseph S Pagano, Christopher B Whitehurst
Epstein-Barr Virus (EBV) infection and lytic replication are known to induce a cellular DNA damage response. Previously we showed that the virally encoded BPLF1 protein interacts with and regulates several members of the translesion synthesis pathway (TLS), a DNA damage tolerance pathway, and that these cellular factors enhance viral infectivity. BPLF1 is a late lytic cycle gene, but the protein is also packaged in the viral tegument indicating that BPLF1 may function both early and late during infection. BPLF1 expresses deubiquitinating activity that is strictly conserved across the Herpesviridae; mutation of the active-site cysteine results in loss of enzymatic activity...
July 19, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28710267/increased-processivity-misincorporation-and-nucleotide-incorporation-efficiency-in-sulfolobus-solfataricus-dpo4-thumb-domain-mutants
#18
Li Wang, Chenchen Liang, Jing Wu, Liming Liu, Keith E J Tyo
The present study aimed to increase the processivity of Sulfolobus solfataricus DNA polymerase Dpo4. Protein engineering and bioinformatics were used to compile a library of potential Dpo4 mutation sites. Ten potential mutants were identified and constructed. A primer extension assay was used to evaluate the processivity of Dpo4 mutants. Thumb (A181D) and finger (E63K) domain mutants showed a processivity of 20 and 19 nucleotides (nt), respectively. A little finger domain mutant (I248Y) exhibited a processivity of 17 nt, only 1 nt more than wild-type Dpo4...
September 15, 2017: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/28668126/analyzing-the-catalytic-activities-and-interactions-of-eukaryotic-translesion-synthesis-polymerases
#19
Kyle T Powers, M Todd Washington
Translesion synthesis is the process by which nonclassical DNA polymerases bypass DNA damage during DNA replication. Cells possess a variety of nonclassical polymerases, each one is specific for incorporating nucleotides opposite to one or more closely related DNA lesions, called its cognate lesions. In this chapter, we discuss a variety of approaches for probing the catalytic activities and the protein-protein interactions of nonclassical polymerases. With respect to their catalytic activities, we discuss polymerase assays, steady-state kinetics, and presteady-state kinetics...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28666590/regulation-of-dna-damage-tolerance-in-mammalian-cells-by-post-translational-modifications-of-pcna
#20
REVIEW
Rie Kanao, Chikahide Masutani
DNA damage tolerance pathways, which include translesion DNA synthesis (TLS) and template switching, are crucial for prevention of DNA replication arrest and maintenance of genomic stability. However, these pathways utilize error-prone DNA polymerases or template exchange between sister DNA strands, and consequently have the potential to induce mutations or chromosomal rearrangements. Post-translational modifications of proliferating cell nuclear antigen (PCNA) play important roles in controlling these pathways...
June 21, 2017: Mutation Research
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