DNA repair mutants defining G2 checkpoint pathways in Schizosaccharomyces pombe.

Al‐Khodairy, Fahad; Carr, Antony

doi:10.1002/j.1460-2075.1992.tb05179.x

Cited by 400 publications

(311 citation statements)

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“…S. pombe strains disrupted at the rhp51, rad13, or rad2 locus by ura4 insertion were generated in the laboratory of A. M. Carr (Sussex University, Sussex, United Kingdom) and kindly given to us by T. Enoch (Harvard Medical School, Boston, Mass.) (1,35); all three strains were disrupted with the ura4 gene and able to grow in the absence of uracil. ura4-D18 leu1-32 S. pombe (designated strain TE236) obtained from T. Enoch) was used as the wild type for DNA repair.…”

Section: Methodsmentioning

confidence: 99%

Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

Memişoğlu

Samson

2000

J Bacteriol

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DNA damage is unavoidable, and organisms across the evolutionary spectrum possess DNA repair pathways that are critical for cell viability and genomic stability. To understand the role of base excision repair (BER) in protecting eukaryotic cells against alkylating agents, we generated Schizosaccharomyces pombe strains mutant for the mag1 3-methyladenine DNA glycosylase gene. We report that S. pombe mag1 mutants have only a slightly increased sensitivity to methylation damage, suggesting that Mag1-initiated BER plays a surprisingly minor role in alkylation resistance in this organism. We go on to show that other DNA repair pathways play a larger role than BER in alkylation resistance. Mutations in genes involved in nucleotide excision repair (rad13) and recombinational repair (rhp51) are much more alkylation sensitive than mag1 mutants. In addition, S. pombe mutant for the flap endonuclease rad2 gene, whose precise function in DNA repair is unclear, were also more alkylation sensitive than mag1 mutants. Further, mag1 and rad13 interact synergistically for alkylation resistance, and mag1 and rhp51 display a surprisingly complex genetic interaction. A model for the role of BER in the generation of alkylation-induced DNA strand breaks in S. pombe is discussed.DNA damage emanates from the inherent chemical instability of nucleic acids, from errors made by DNA polymerase during DNA replication, and from exposure to DNA-damaging agents present in the environment or produced by certain endogenous cellular processes (reviewed in reference 15). All organisms possess a panel of DNA repair mechanisms to repair damaged DNA. DNA excision repair pathways recognize and remove damaged segments from one DNA strand and then resynthesize new DNA, using the opposing undamaged strand as a template. Excision repair includes base excision repair (BER) and nucleotide excision repair (NER). An alternative approach to handling damaged DNA is by recombinational repair. These DNA repair pathways have been best characterized in Escherichia coli, but analogous pathways have been found in all organisms examined to date (15).BER initiation occurs by the action of DNA glycosylases that recognize specific types of damaged or abnormal DNA bases and cleave the glycosylic bond linking the base to the sugarphosphate backbone. DNA glycosylases recognize bases such as uracil, deaminated adenine (hypoxanthine), and certain alkylated and oxidized purines and pyrimidines (reviewed in references 10, 15, 21, 31, and 47). Releasing a damaged base from the DNA produces an apurinic/apyrimidinic (AP) site, and it is worth noting that AP sites are themselves a form of DNA damage. In addition to being generated by DNA glycosylases, AP sites can be formed spontaneously. AP endonucleases (which cleave 5Ј to the AP site) or AP lyases (which cleave 3Ј to the AP site) cleave the DNA backbone adjacent to the AP site. AP endonuclease produces a 5Ј-deoxyribose phosphate moiety, which must be removed to allow subsequent DNA ligation; removal occurs by the action of deoxyr...

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Section: Methodsmentioning

confidence: 99%

Contribution of Base Excision Repair, Nucleotide Excision Repair, and DNA Recombination to Alkylation Resistance of the Fission Yeast Schizosaccharomyces pombe

Memişoğlu

Samson

2000

J Bacteriol

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“…1A, bottom) is activated by treatment with hydroxyurea, which inhibits DNA replication, and this checkpoint also controls the G2 to M transition through inhibitory phosphorylation of Cdc2 [10]. Parts of this DNA replication checkpoint are shared with the DNA damage checkpoint as Rad1, Rad3, Rad9, Rad17, Rad26 and Hus1 are required for both checkpoints in fission yeast [21]. The same 9-1-1 and Rad3-Rad26 checkpoint protein complexes may associate with the DNA replication complex [13].…”

Section: Cell Cycle G2/m Controls and Check-pointsmentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

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“…The checkpoint rad genes include rad1 sp , rad3 sp , rad9 sp , rad17 sp , rad26 sp , and hus1 sp . These are required for all the known S. pombe DNA checkpoints [3,13,14]. At the very least, the checkpoint rad gene products serve as signal transducers between the primary checkpoint signal and the cell cycle machinery.…”

Section: The Schizosaccharomyces Pombe G 2 Dna Damage Checkpointmentioning

confidence: 99%

“…G 2 /M checkpoints prevent cells from passing through mitosis. In some cases, such as the G 2 DNA-damage checkpoint in S. pombe and vertebrates, cells arrest in G 2 [3,4], while in others, such as the DNA-damage and spindle checkpoints in S. cerevisiae, cells arrest during M phase at the metaphase to anaphase transition [5,6]. But, as near as we can tell, the general purpose of G 2 /M checkpoints is to prevent sister chromatid separation which, in the presence of either DNA damage or incomplete replication, is the irreversible step that turns a temporary setback into a lethal event (Figure 1a).…”

Section: Introductionmentioning

confidence: 99%