Spelling suggestions: "subject:"DNA replication -- 95regulation."" "subject:"DNA replication -- a.regulation.""
1 |
THE ROLE OF GENES 39, 52, 58-61 AND 60 IN BACTERIOPHAGE-T4 REPLICATIONMufti, Siraj-ul-Islam, 1934- January 1973 (has links)
No description available.
|
2 |
Cell cycle regulation of DNA precursor accumulation in the yeast Saccharomyces cerevisiaeKoc, Ahmet 11 June 2002 (has links)
In budding yeast, many of the genes that encode enzymes required for DNA
precursor synthesis (MCB genes) are expressed under cell cycle control in late
G1/S. The relationship between MCB gene expression, dNTP synthesis and DNA
synthesis was investigated by using �� factor-synchronized Saccharomyces
cerevisiae. The levels of all four dNTPs increased several-fold when cells crossed
the G1/S boundary. An even larger increase in the dNTP pools occurred at G1/S
when replication initiation was blocked by incubating synchronized dbf4 mutants at
the nonpermissive temperature. Thus, dNTP accumulation at G1/S was not
dependent on replication initiation. Similarly, MCB gene induction at G1/S was
also independent of replication initiation. The accumulation of dNTPs at G1/S was
dependent on Swi6, a protein known to be required for normal MCB gene
regulation during the cell cycle. Treatment with hydroxyurea, an inhibitor of
ribonucleotide reductase, blocked DNA synthesis and prevented the increase in
dNTP levels that normally occurred at G1/S, however, it did not exhaust the basal
levels of any of the four dNTPs. The mechanism responsible for replication arrest
despite the persistence of dNTPs was not dependent on the checkpoint protein
Rad53, as rad53 mutants also failed to exhaust basal dNTPs when incubated in HU.
The inhibitory effect of HU on DNA synthesis was bypassed when dbf4 cells were
allowed to pre-accumulate dNTPs at 37��C before being released to the permissive
temperature in the presence of HU. Accumulation of dNTPs at G1/S was not a
prerequisite for replication initiation, as dbf4 cells incubated in HU at 25��C were
able to initiate replication when cells were switched to the nonpermissive
temperature and HU was removed. The results indicate that DNA chain elongation
in yeast requires a critical dNTP threshold, below which replication forks are
completely arrested. Cells lacking a functional thioredoxin system were deficient
in dNTP synthesis. The rate of accumulation was significantly lower in ��trr1
mutants lacking thioredoxin reductase, and dNTP accumulation at G1/S did not
occur at all in ��trxl ��trx2 double mutants lacking thioredoxin. The results suggest
that thioredoxin serves as the electron donor for ribonucleotide reductase during
DNA precursor synthesis in yeast. / Graduation date: 2003
|
3 |
Regulation of the Bloom's syndrome proteinNorth, Phillip January 2012 (has links)
In response to DNA damage, the ATM and ATR kinases proliferate a signal that is transduced, either directly or via Chk2 and Chk1, to effector proteins, forming the DNA damage response (DDR). The effector proteins delay cell cycle progression, through checkpoints, and activate specific DNA repair mechanisms essential for preserving genome integrity and preventing cancer formation. Bloom's syndrome (BS) patients, which lack the BLM protein show genome instability and have a predisposition to cancer. BLM is phosphorylated by the DDR kinases ATM, ATR and Chk1. These phosphorylation events are essential for BLM to maintain replication fork integrity, preserve the S phase checkpoint and activate BLM to interact with other DDR proteins. In this study I have shown that BLM, isolated from mitotic cells, is phosphorylated on amino acid residue serine 26 (S26). BS cells lacking native BLM, but expressing a variant of BLM protein that cannot be phosphorylated at S26, fail to fully activate the G2/M checkpoint following UV irradiation or treatment with inhibitors of DNA topoisomerase H. Consequently, these cells are more sensitive to killing by these agents than are BS cells expressing wildtype BLM. The Chk1 and Aurora B kinases are able to phosphorylate BLM on S26 in vitro. Moreover, loss of Aurora B kinase activity leads to reduction of S26 phosphorylation in mitotic cells. Cells treated with inhibitors of Aurora B fail to fully active the G2/M checkpoint after UV DNA damage. Taken together, these data suggest, that Aurora B kinase phosphorylates BLM on S26 and that this is required to fully activate the G2/M checkpoint.
|
4 |
Regulation of mouse ribonucleotide reductase by allosteric effector-substrate interplay and hypoxiaChimploy, Korakod 12 June 2002 (has links)
In order to maintain genetic stability in eukaryotes, tight regulation of the
relative sizes of deoxyribonucleoside triphosphate (dNTP) levels inside the cell is
essential for optimal fidelity of DNA replication. Ribonucleotide reductase (RNR)
is the enzyme responsible for proportional production of DNA precursors. Studies
on regulation of this enzyme, the focus of this thesis, are important because
mutations affecting RNR control mechanisms result in dNTP pool imbalance, thus
promoting mutagenesis.
By using mouse RNR as a model for mammalian forms of the enzyme,
three major factors--allosteric effectors, rNDP substrate concentrations, and
hypoxic conditions--that influence the substrate specificity of RNR have been
investigated. Allosteric regulation has been studied by the four-substrate assay,
which permits simultaneous monitoring of the four reactions catalyzed by this
enzyme in one reaction mixture. Individual dNTPs affect the four activities
differentially in a concentration-dependent manner with discrete effects of dTTP
and dGTP on reduction of ADP and GDP, respectively. Ribonucleoside
diphosphate (rNDP) substrate concentrations are equally important, as their
variations lead to different product ratios. Results from nucleotide binding assays
indicate that rNDPs directly influence binding of dNTP effectors at the specificity
site, one of the two classes of allosteric sites, whereas ADP has an indirect effect,
displacing other substrates at the catalytic site and consequently removing effects
of those substrates upon dNTP binding. Hence, this is the first evidence of a two-way
communication between the catalytic site and the specificity site. Oxygen
limitation also plays an important role in controlling the enzyme specificity.
Reactivation of the enzyme at different oxygen tensions, after treatment of the
enzyme with hydroxyurea (HU) followed by removal of HU, reveals a distinct
sensitivity of GDP reductase to low 0��� levels. Although the basis for specific
inhibition of GDP reduction remains to be determined, some possibilities have been
ruled out.
This research proves that in addition to allosteric regulation by nucleoside
triphosphates, mouse RNR is also controlled by other factors. Since these
components can simultaneously exert their effects upon enzyme specificity,
complex regulatory patterns of RNR to provide a proportional supply of the DNA
building blocks in vivo are suggested. / Graduation date: 2003
|
5 |
The induction of apoptosis by the E2F1 transcription factor and the emergence of a role for E2F1 in the DNA double strand break responsePowers, John Thomas 28 August 2008 (has links)
Not available / text
|
6 |
Identification of novel small molecule inhibitors of proteins required for genomic maintenance and stabilityShuck, Sarah C. 29 July 2010 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Targeting uncontrolled cell proliferation and resistance to DNA damaging chemotherapeutics using small molecule inhibitors of proteins involved in these pathways has significant potential in cancer treatment. Several proteins involved in genomic maintenance and stability have been implicated both in the development of cancer and the response to chemotherapeutic treatment. Replication Protein A, RPA, the eukaryotic single-strand DNA binding protein, is essential for genomic maintenance and stability via roles in both DNA replication and repair. Xeroderma Pigmentosum Group A, XPA, is required for nucleotide excision repair, the main pathway cells employ to repair bulky DNA adducts. Both of these proteins have been implicated in tumor progression and chemotherapeutic response. We have identified a novel small molecule that inhibits the in vitro and cellular ssDNA binding activity of RPA, prevents cell cycle progression, induces cytotoxicity and increases the efficacy of chemotherapeutic DNA damaging agents. These results provide new insight into the mechanism of RPA-ssDNA interactions in chromosome maintenance and stability. We have also identified small molecules that prevent the XPA-DNA interaction, which are being investigated for cellular and tumor activity. These results demonstrate the first molecularly targeted eukaryotic DNA binding inhibitors and reveal the utility of targeting a protein-DNA interaction as a therapeutic strategy for cancer treatment.
|
7 |
Cascades of genetic instability resulting from compromised break-induced replicationVasan, Soumini January 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Break-induced replication (BIR) is a mechanism to repair double-strand breaks
(DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here I demonstrate that HC formation results from the interruption of BIR caused by a defective replisome or premature onset of mitosis. Additionally, I document the existence of half crossover instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. I postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer.
|
Page generated in 0.1519 seconds