DNA replication licensing factor

Chong, James P. J.; Blow, J. Julian

doi:10.1007/978-1-4615-5873-6_8

Cited by 15 publications

(12 citation statements)

References 68 publications

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“…Similar to nickel, chromium also up-regulated il1b, c/ebp, and atf3 (Figure 5B and Additional file 1: Table S1). Chromium also up-regulated cell cycle regulation and apoptosis genes not enhanced in the other metals, including genes involved in the G 1 /S and G 2 /M cell-cycle checkpoints ( ccne2 , rrm2 ; Additional file 1: Table S1 and Figure 5B; [89]) and in the RAD6-dependent DNA repair pathway ( pcna ) [90,91] (Figure 5B). The transcription factor p53 was also up-regulated (Figure 5A), which mediates expression of protective genes that repair damaged DNA, power the immune system, arrest the proliferation of damaged cells, and induce apoptosis [92], as well as guards the cell-cycle checkpoint by inducing apoptosis under conditions of excessive oxidative stress and DNA damage [93].…”

Section: Resultsmentioning

confidence: 99%

Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

Hussainzada¹,

Lewis

Baer

et al. 2014

BMC Pharmacol Toxicol

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BackgroundA convergence of technological breakthroughs in the past decade has facilitated the development of rapid screening tools for biomarkers of toxicant exposure and effect. Platforms using the whole adult organism to evaluate the genome-wide response to toxicants are especially attractive. Recent work demonstrates the feasibility of this approach in vertebrates using the experimentally robust zebrafish model. In the present study, we evaluated gene expression changes in whole adult male zebrafish following an acute 24 hr high dose exposure to three metals with known human health risks. Male adult zebrafish were exposed to nickel chloride, cobalt chloride or sodium dichromate concentrations corresponding to their respective 96 hr LC20, LC40 and LC60. Histopathology was performed on a subset of metal-exposed zebrafish to phenotypically anchor transcriptional changes associated with each metal.ResultsComparative analysis identified subsets of differentially expressed transcripts both overlapping and unique to each metal. Application of gene ontology (GO) and transcription factor (TF) enrichment algorithms revealed a number of key biological processes perturbed by metal poisonings and the master transcriptional regulators mediating gene expression changes. Metal poisoning differentially activated biological processes associated with ribosome biogenesis, proteosomal degradation, and p53 signaling cascades, while repressing oxygen-generating pathways associated with amino acid and lipid metabolism. Despite appreciable effects on gene regulation, nickel poisoning did not induce any morphological alterations in male zebrafish organs and tissues. Histopathological effects of cobalt remained confined to the olfactory system, while chromium targeted the gills, pharynx, and intestinal mucosa. A number of enriched transcription factors mediated the observed gene response to metal poisoning, including known targets such as p53, HIF1α, and the myc oncogene, and novel regulatory factors such as XBP1, GATA6 and HNF3β.ConclusionsThis work uses an experimentally innovative approach to capture global responses to metal poisoning and provides mechanistic insights into metal toxicity.

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Section: Resultsmentioning

confidence: 99%

Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

Hussainzada¹,

Lewis

Baer

et al. 2014

BMC Pharmacol Toxicol

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“…A cold-sensitive allele of MCM4 that blocked DNA replication at nonpermissive temperatures was isolated (102). The identification of the six Mcm proteins as being active components of the Xenopus "replication licensing factor," a protein postulated to couple DNA replication to cell cycle progression (20), provided biochemical verification (41,251).…”

Section: Discovery Of the MCM Genes: Involvement In Dna Replicationmentioning

confidence: 99%

The Mcm Complex: Unwinding the Mechanism of a Replicative Helicase

Bochman

Schwacha

2009

Microbiol Mol Biol Rev

287

278

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SUMMARY The Mcm2-7 complex serves as the eukaryotic replicative helicase, the molecular motor that both unwinds duplex DNA and powers fork progression during DNA replication. Consistent with its central role in this process, much prior work has illustrated that Mcm2-7 loading and activation are landmark events in the regulation of DNA replication. Unlike any other hexameric helicase, Mcm2-7 is composed of six unique and essential subunits. Although the unusual oligomeric nature of this complex has long hampered biochemical investigations, recent advances with both the eukaryotic as well as the simpler archaeal Mcm complexes provide mechanistic insight into their function. In contrast to better-studied homohexameric helicases, evidence suggests that the six Mcm2-7 complex ATPase active sites are functionally distinct and are likely specialized to accommodate the regulatory constraints of the eukaryotic process.

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“…The MCM complex (comprised of Mcm2-7 subunits) is the heterohexameric ATPase core of the replicative helicase that is loaded onto DNA at multiple sites only during G1-phase in a process called licensing, which allows for one round of DNA replication per cycle (6-8). Certain MCM complexes are chosen to function as active helicases upon recruitment of C dc45 to M CM cores, along with the G INS complex, producing what is referred to as a CMG helicase (9-11).…”

Section: Introductionmentioning

confidence: 99%

Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil

Bryant

Elias

McCarthy

et al. 2015

Molecular Cancer Research

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Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil (5-FU) are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S-phase. The excess MCM complexes function as back-up initiation sites under conditions of replicative stress. The current study provides definitive evidence that co-suppression of the excess/back-up MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared to drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are non-tumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when co-suppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. Implications These studies demonstrate that suppressing the back-up complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers.

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DNA replication licensing factor

Cited by 15 publications

References 68 publications

Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

Whole adult organism transcriptional profiling of acute metal exposures in male Zebrafish

The Mcm Complex: Unwinding the Mechanism of a Replicative Helicase

Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5-Fluorouracil

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