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https://www.readbyqxmd.com/read/28430596/snm1b-apollo-in-the-dna-damage-response-and-telomere-maintenance
#1
REVIEW
Maren Schmiester, Ilja Demuth
hSNM1B/Apollo is a member of the highly conserved β-CASP subgroup within the MBL superfamily of proteins. It interacts with several DNA repair proteins and functions within the Fanconi anemia pathway in response to DNA interstrand crosslinks. As a shelterin accessory protein, hSNM1B/Apollo is also vital for the generation and maintenance of telomeric overhangs. In this review, we will summarize studies on hSNM1B/Apollo's function, including its contribution to DNA damage signaling, replication fork maintenance, control of topological stress and telomere protection...
April 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28427716/xenopus-egg-extract-a-powerful-tool-to-study-genome-maintenance-mechanisms
#2
REVIEW
Wouter S Hoogenboom, Daisy Klein Douwel, Puck Knipscheer
DNA repair pathways are crucial to maintain the integrity of our genome and prevent genetic diseases such as cancer. There are many different types of DNA damage and specific DNA repair mechanisms have evolved to deal with these lesions. In addition to these repair pathways there is an extensive signaling network that regulates processes important for repair, such as cell cycle control and transcription. Despite extensive research, DNA damage repair and signaling are not fully understood. In vitro systems such as the Xenopus egg extract system, have played, and still play, an important role in deciphering the molecular details of these processes...
April 17, 2017: Developmental Biology
https://www.readbyqxmd.com/read/28427283/break-induced-replication-in-eukaryotes-mechanisms-functions-and-consequences
#3
Cynthia J Sakofsky, Anna Malkova
Break-induced replication (BIR) is an important pathway specializing in repair of one-ended double-strand DNA breaks (DSBs). This type of DSB break typically arises at collapsed replication forks or at eroded telomeres. BIR initiates by invasion of a broken DNA end into a homologous template followed by initiation of DNA synthesis that can proceed for hundreds of kilobases. This synthesis is drastically different from S-phase replication in that instead of a replication fork, BIR proceeds via a migrating bubble and is associated with conservative inheritance of newly synthesized DNA...
April 21, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28425306/therapeutic-targeting-and-patient-selection-for-cancers-with-homologous-recombination-defects
#4
Francien Talens, Mathilde Jalving, Jourik A Gietema, Marcel A T M van Vugt
DNA double-strand breaks (DSBs) are toxic DNA lesions that can be repaired by non-homologous end-joining (NHEJ) or homologous recombination (HR). Mutations in HR genes elicit a predisposition to cancer; yet, they also result in increased sensitivity to certain DNA damaging agents and poly (ADP-ribose) polymerase (PARP) inhibitors. To optimally implement PARP inhibitor treatment, it is important that patients with HR-deficient tumors are adequately selected. Areas covered: Herein, the authors describe the HR pathway mechanistically and review the treatment of HR-deficient cancers, with a specific focus on PARP inhibition for BRCA1/2-mutated breast and ovarian cancer...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28423907/effects-of-active-site-mutations-on-specificity-of-nucleobase-binding-in-human-dna-polymerase-%C3%AE
#5
Melek N Ucisik, Sharon Hammes-Schiffer
Human DNA polymerase η (Pol η) plays a vital role in protection against skin cancer caused by damage from ultraviolet light. This enzyme rescues stalled replication forks at cyclobutane thymine-thymine dimers (TTDs) by inserting nucleotides opposite these DNA lesions. Residue R61 is conserved in the Pol η enzymes across species, but the corresponding residue, as well as its neighbor S62, is different in other Y-family polymerases, Pol ι and Pol κ. Herein, R61 and S62 are mutated to their Pol ι and Pol κ counterparts...
April 20, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28423595/dutpase-inhibition-augments-replication-defects-of-5-fluorouracil
#6
Anna Hagenkort, Cynthia B J Paulin, Matthieu Desroses, Antonio Sarno, Elisée Wiita, Oliver Mortusewicz, Tobias Koolmeister, Olga Loseva, Ann-Sofie Jemth, Ingrid Almlöf, Evert Homan, Thomas Lundbäck, Anna-Lena Gustavsson, Martin Scobie, Thomas Helleday
The antimetabolite 5-Fluorouracil (5-FU) is used in the treatment of various forms of cancer and has a complex mode of action. Despite 6 decades in clinical application the contribution of 5-FdUTP and dUTP [(5-F)dUTP] and 5-FUTP misincorporation into DNA and RNA respectively, for 5-FU-induced toxicity is still under debate.This study investigates DNA replication defects induced by 5-FU treatment and how (5-F)dUTP accumulation contributes to this effect. We reveal that 5-FU treatment leads to extensive problems in DNA replication fork progression, causing accumulation of cells in S-phase, DNA damage and ultimately cell death...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419835/the-architecture-and-function-of-the-chromatin-replication-machinery
#7
REVIEW
Thomas Cr Miller, Alessandro Costa
Genomic DNA in eukaryotic cells is packaged into nucleosome arrays. During replication, nucleosomes need to be dismantled ahead of the advancing replication fork and reassembled on duplicated DNA. The architecture and function of the core replisome machinery is now beginning to be elucidated, with recent insights shaping our view on DNA replication processes. Simultaneously, breakthroughs in our mechanistic understanding of epigenetic inheritance allow us to build new models of how histone chaperones integrate with the replisome to reshuffle nucleosomes...
April 15, 2017: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/28416680/using-microsecond-single-molecule-fret-to-determine-the-assembly-pathways-of-t4-ssdna-binding-protein-onto-model-dna-replication-forks
#8
Carey Phelps, Brett Israels, Davis Jose, Morgan C Marsh, Peter H von Hippel, Andrew H Marcus
DNA replication is a core biological process that occurs in prokaryotic cells at high speeds (∼1 nucleotide residue added per millisecond) and with high fidelity (fewer than one misincorporation event per 10(7) nucleotide additions). The ssDNA binding protein [gene product 32 (gp32)] of the T4 bacteriophage is a central integrating component of the replication complex that must continuously bind to and unbind from transiently exposed template strands during DNA synthesis. We here report microsecond single-molecule FRET (smFRET) measurements on Cy3/Cy5-labeled primer-template (p/t) DNA constructs in the presence of gp32...
April 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28416269/dna-protein-crosslink-proteolysis-repair
#9
REVIEW
Bruno Vaz, Marta Popovic, Kristijan Ramadan
Proteins that are covalently bound to DNA constitute a specific type of DNA lesion known as DNA-protein crosslinks (DPCs). DPCs represent physical obstacles to the progression of DNA replication. If not repaired, DPCs cause stalling of DNA replication forks that consequently leads to DNA double-strand breaks, the most cytotoxic DNA lesion. Although DPCs are common DNA lesions, the mechanism of DPC repair was unclear until now. Recent work unveiled that DPC repair is orchestrated by proteolysis performed by two distinct metalloproteases, SPARTAN in metazoans and Wss1 in yeast...
April 14, 2017: Trends in Biochemical Sciences
https://www.readbyqxmd.com/read/28415748/the-spi1-pu-1-transcription-factor-accelerates-replication-fork-progression-by-increasing-pp1-phosphatase-in-leukemia
#10
Pauline Rimmelé, Michela Esposito, Laure Delestré, Jean-Hugues Guervilly, Maya Ridinger-Saison, Emmanuelle Despras, Françoise Moreau-Gachelin, Filippo Rosselli, Christel Guillouf
Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks...
March 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/28410592/study-of-sv40-large-t-antigen-nucleotide-specificity-for-dna-unwinding
#11
Damian Wang, Ana Lucia Álvarez-Cabrera, Xiaojiang S Chen
BACKGROUND: Simian Virus 40 (SV40) Large Tumor Antigen (LT) is an essential enzyme that plays a vital role in viral DNA replication in mammalian cells. As a replicative helicase and initiator, LT assembles as a double-hexamer at the SV40 origin to initiate genomic replication. In this process, LT converts the chemical energy from ATP binding and hydrolysis into the mechanical work required for unwinding replication forks. It has been demonstrated that even though LT primarily utilizes ATP to unwind DNA, other NTPs can also support low DNA helicase activity...
April 14, 2017: Virology Journal
https://www.readbyqxmd.com/read/28407100/seqa-structures-behind-escherichia-coli-replication-forks-affect-replication-elongation-and-restart-mechanisms
#12
Ida Benedikte Pedersen, Emily Helgesen, Ingvild Flåtten, Solveig Fossum-Raunehaug, Kirsten Skarstad
The SeqA protein binds hemi-methylated GATC sites and forms structures that sequester newly replicated origins and trail the replication forks. Cells that lack SeqA display signs of replication fork disintegration. The broken forks could arise because of over-initiation (the launching of too many forks) or lack of dynamic SeqA structures trailing the forks. To confirm one or both of these possible mechanisms, we compared two seqA mutants with the oriCm3 mutant. The oriCm3 mutant over-initiates because of a lack of origin sequestration but has wild-type SeqA protein...
April 12, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28402439/chromodomain-protein-cdyl-is-required-for-transmission-restoration-of-repressive-histone-marks
#13
Yongqing Liu, Shumeng Liu, Shuai Yuan, Huajing Yu, Yu Zhang, Xiaohan Yang, Guojia Xie, Zhe Chen, Wanjin Li, Bosen Xu, Luyang Sun, Yongfeng Shang, Jing Liang
Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is critical for the maintenance of cell identity. We report here that chromodomain Y-like protein (CDYL), a chromodomain-containing transcription corepressor, is physically associated with chromatin assembly factor 1 (CAF-1) and the replicative helicase MCM complex. We showed that CDYL bridges CAF-1 and MCM, facilitating histone transfer and deposition during DNA replication. We demonstrated that CDYL recruits histone-modifying enzymes G9a, SETDB1, and EZH2 to replication forks, leading to the addition of H3K9me2/3 and H3K27me2/3 on newly deposited histone H3...
April 10, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/28396594/human-primpol-activity-is-enhanced-by-rpa
#14
María I Martínez-Jiménez, Antonio Lahera, Luis Blanco
Human PrimPol is a primase belonging to the AEP superfamily with the unique ability to synthesize DNA primers de novo, and a non-processive DNA polymerase able to bypass certain DNA lesions. PrimPol facilitates both mitochondrial and nuclear replication fork progression either acting as a conventional TLS polymerase, or repriming downstream of blocking lesions. In vivo assays have shown that PrimPol is rapidly recruited to sites of DNA damage by interaction with the human replication protein A (RPA). In agreement with previous findings, we show here that the higher affinity of RPA for ssDNA inhibits PrimPol activities in short ssDNA templates...
April 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28394262/mutant-p53-establishes-targetable-tumor-dependency-by-promoting-unscheduled-replication
#15
Shilpa Singh, Catherine A Vaughan, Rebecca A Frum, Steven R Grossman, Sumitra Deb, Swati Palit Deb
Gain-of-function (GOF) p53 mutations are observed frequently in most intractable human cancers and establish dependency for tumor maintenance and progression. While some of the genes induced by GOF p53 have been implicated in more rapid cell proliferation compared with p53-null cancer cells, the mechanism for dependency of tumor growth on mutant p53 is unknown. This report reveals a therapeutically targetable mechanism for GOF p53 dependency. We have shown that GOF p53 increases DNA replication origin firing, stabilizes replication forks, and promotes micronuclei formation, thus facilitating the proliferation of cells with genomic abnormalities...
April 10, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28389464/chromatin-determinants-impart-camptothecin-sensitivity
#16
Fabio Puddu, Israel Salguero, Mareike Herzog, Nicola J Geisler, Vincenzo Costanzo, Stephen P Jackson
Camptothecin-induced locking of topoisomerase 1 on DNA generates a physical barrier to replication fork progression and creates topological stress. By allowing replisome rotation, absence of the Tof1/Csm3 complex promotes the conversion of impending topological stress to DNA catenation and causes camptothecin hypersensitivity. Through synthetic viability screening, we discovered that histone H4 K16 deacetylation drives the sensitivity of yeast cells to camptothecin and that inactivation of this pathway by mutating H4 K16 or the genes SIR1-4 suppresses much of the hypersensitivity of tof1∆ strains towards this agent...
April 7, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28386413/threshold-effect-of-growth-rate-on-population-variability-of-escherichia-coli-cell-lengths
#17
Manasi S Gangan, Chaitanya A Athale
A long-standing question in biology is the effect of growth on cell size. Here, we estimate the effect of Escherichia coli growth rate (r) on population cell size distributions by estimating the coefficient of variation of cell lengths (CVL) from image analysis of fixed cells in DIC microscopy. We find that the CVL is constant at growth rates less than one division per hour, whereas above this threshold, CVL increases with an increase in the growth rate. We hypothesize that stochastic inhibition of cell division owing to replication stalling by a RecA-dependent mechanism, combined with the growth rate threshold of multi-fork replication (according to Cooper and Helmstetter), could form the basis of such a threshold effect...
February 2017: Royal Society Open Science
https://www.readbyqxmd.com/read/28386108/structural-insight-into-the-specific-dna-template-binding-to-dnag-primase-in-bacteria
#18
Yingqin Zhou, Hao Luo, Zhongchuan Liu, Mu Yang, Xiaoyun Pang, Fei Sun, Ganggang Wang
Bacterial primase initiates the repeated synthesis of short RNA primers that are extended by DNA polymerase to synthesize Okazaki fragments on the lagging strand at replication forks. It remains unclear how the enzyme recognizes specific initiation sites. In this study, the DnaG primase from Bacillus subtilis (BsuDnaG) was characterized and the crystal structure of the RNA polymerase domain (RPD) was determined. Structural comparisons revealed that the tethered zinc binding domain plays an important role in the interactions between primase and specific template sequence...
April 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28383499/eukaryotic-replicative-helicase-subunit-interaction-with-dna-and-its-role-in-dna-replication
#19
REVIEW
Matthew P Martinez, Amanda L Wacker, Irina Bruck, Daniel L Kaplan
The replicative helicase unwinds parental double-stranded DNA at a replication fork to provide single-stranded DNA templates for the replicative polymerases. In eukaryotes, the replicative helicase is composed of the Cdc45 protein, the heterohexameric ring-shaped Mcm2-7 complex, and the tetrameric GINS complex (CMG). The CMG proteins bind directly to DNA, as demonstrated by experiments with purified proteins. The mechanism and function of these DNA-protein interactions are presently being investigated, and a number of important discoveries relating to how the helicase proteins interact with DNA have been reported recently...
April 6, 2017: Genes
https://www.readbyqxmd.com/read/28380422/the-dominant-role-of-proofreading-exonuclease-activity-of-replicative-polymerase-%C3%AE%C2%B5-in-cellular-tolerance-to-cytarabine-ara-c
#20
Masataka Tsuda, Kazuhiro Terada, Masato Ooka, Koji Kobayashi, Hiroyuki Sasanuma, Ryo Fujisawa, Toshiki Tsurimoto, Junpei Yamamoto, Shigenori Iwai, Kei Kadoda, Remi Akagawa, Shar-Yin Naomi Huang, Yves Pommier, Julian E Sale, Shunichi Takeda, Kouji Hirota
Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis...
March 23, 2017: Oncotarget
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