The Rb/E2F pathway and Ras activation regulate RecQ helicase gene expression

2008 ◽  
Vol 412 (2) ◽  
pp. 299-306 ◽  
Author(s):  
Yongqing Liu ◽  
Shahenda El-Naggar ◽  
Brian Clem ◽  
Jason Chesney ◽  
Douglas C. Dean
Keyword(s):  
Dna Replication ◽  
Family Members ◽  
Dna Helicase ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Ras Activation ◽  
Oncogenic Mutations ◽  
Helicase Gene ◽  
Cell Cycle Pathway ◽  
Premature Aging Syndromes

Disruption of the Rb (retinoblastoma protein)/E2F cell-cycle pathway and Ras activation are two of the most frequent events in cancer, and both of these mutations place oncogenic stress on cells to increase DNA replication. In the present study, we demonstrate that these mutations have an additive effect on induction of members of the RecQ DNA helicase family. RecQ activity is important for genomic stability, initiation of DNA replication and telomere maintenance, and mutation of the BLM (Bloom's syndrome gene), WRN (Werner's syndrome gene) or RECQL4 (Rothmund–Thomson syndrome gene) family members leads to premature aging syndromes characterized by genetic instability and telomere loss. RecQ family members are frequently overexpressed in cancers, and overexpression of BLM has been shown to cause telomere elongation. Concomitant with induction of RecQ genes in response to Rb family mutation and Ras activation, we show an increase in the number of telomeric repeats. We suggest that this induction of RecQ genes in response to common oncogenic mutations may explain the up-regulation of the genes seen in cancers, and it may provide a means for transformed cells to respond to an increased demand for DNA replication.

scholarly journals Involvement of a replicative DNA helicase of bacteriophage T4 in DNA recombination.

Genetics ◽  
1994 ◽  
Vol 138 (2) ◽  
pp. 247-252 ◽  
Author(s):  
T Yonesaki
Keyword(s):  
Dna Replication ◽  
Dna Synthesis ◽  
Genetic Recombination ◽  
Bacteriophage T4 ◽  
Dna Recombination ◽  
Dna Helicase ◽  
Replicative Helicase ◽  
Helicase Gene ◽  
A Subunit ◽  
Lagging Strand

Abstract Bacteriophage T4 gene 41 encodes a replicative DNA helicase that is a subunit of the primosome which is essential for lagging-strand DNA synthesis. A mutation, rrh, was generated and selected in the helicase gene on the basis of limited DNA replication that ceases early. The survival of ultraviolet-irradiated phage and the frequency of genetic recombination are reduced by rrh. In addition, rrh diminishes the production of concatemeric DNA. These results strongly suggest that the gene 41 replicative helicase participates in DNA recombination.

scholarly journals Direct quantification of the translocation activities of Saccharomyces cerevisiae Pif1 helicase

2019 ◽  
Vol 47 (14) ◽  
pp. 7494-7501
Author(s):  
Chen Lu ◽  
Shimin Le ◽  
Jin Chen ◽  
Alicia K Byrd ◽  
Daniela Rhodes ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Genome Stability ◽  
Dna Helicase ◽  
Telomere Maintenance ◽  
The Other ◽  
Biological Processes ◽  
Helicase Activity ◽  
Pif1 Helicase ◽  
Direct Quantification

AbstractSaccharomyces cerevisiae Pif1 (ScPif1) is known as an ATP-dependent DNA helicase that plays critical roles in a number of important biological processes such as DNA replication, telomere maintenance and genome stability maintenance. Besides its DNA helicase activity, ScPif1 is also known as a single-stranded DNA (ssDNA) translocase, while how ScPif1 translocates on ssDNA is unclear. Here, by measuring the translocation activity of individual ScPif1 molecules on ssDNA extended by mechanical force, we identified two distinct types of ssDNA translocation. In one type, ScPif1 moves along the ssDNA track with a rate of ∼140 nt/s in 100 μM ATP, whereas in the other type, ScPif1 is immobilized to a fixed location of ssDNA and generates ssDNA loops against force. Between the two, the mobile translocation is the major form at nanomolar ScPif1 concentrations although patrolling becomes more frequent at micromolar concentrations. Together, our results suggest that ScPif1 translocates on extended ssDNA in two distinct modes, primarily in a ‘mobile’ manner.

scholarly journals The Short Life Span of Saccharomyces cerevisiae sgs1 and srs2 Mutants Is a Composite of Normal Aging Processes and Mitotic Arrest Due to Defective Recombination

Genetics ◽  
2001 ◽  
Vol 157 (4) ◽  
pp. 1531-1542 ◽  
Author(s):  
Mitch McVey ◽  
Matt Kaeberlein ◽  
Heidi A Tissenbaum ◽  
Leonard Guarente
Keyword(s):  
Cell Cycle ◽  
Life Span ◽  
Mitotic Cell ◽  
Dna Helicase ◽  
Premature Aging ◽  
Growth Defect ◽  
Short Life Span ◽  
Single Strand Annealing ◽  
Late Generation ◽  
Strand Annealing

Abstract Evidence from many organisms indicates that the conserved RecQ helicases function in the maintenance of genomic stability. Mutation of SGS1 and WRN, which encode RecQ homologues in budding yeast and humans, respectively, results in phenotypes characteristic of premature aging. Mutation of SRS2, another DNA helicase, causes synthetic slow growth in an sgs1 background. In this work, we demonstrate that srs2 mutants have a shortened life span similar to sgs1 mutants. Further dissection of the sgs1 and srs2 survival curves reveals two distinct phenomena. A majority of sgs1 and srs2 cells stops dividing stochastically as large-budded cells. This mitotic cell cycle arrest is age independent and requires the RAD9-dependent DNA damage checkpoint. Late-generation sgs1 and srs2 cells senesce due to apparent premature aging, most likely involving the accumulation of extrachromosomal rDNA circles. Double sgs1 srs2 mutants are viable but have a high stochastic rate of terminal G2/M arrest. This arrest can be suppressed by mutations in RAD51, RAD52, and RAD57, suggesting that the cell cycle defect in sgs1 srs2 mutants results from inappropriate homologous recombination. Finally, mutation of RAD1 or RAD50 exacerbates the growth defect of sgs1 srs2 cells, indicating that sgs1 srs2 mutants may utilize single-strand annealing as an alternative repair pathway.

scholarly journals Human WRN is an intrinsic inhibitor of progerin, abnormal splicing product of lamin A

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
So-mi Kang ◽  
Min-Ho Yoon ◽  
Su-Jin Lee ◽  
Jinsook Ahn ◽  
Sang Ah Yi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Life Span ◽  
Expression Analysis ◽  
Gene Expression Analysis ◽  
Werner Syndrome ◽  
Genetic Disorder ◽  
Dna Helicase ◽  
Premature Aging ◽  
Lamin A ◽  
Short Life Span

AbstractWerner syndrome (WRN) is a rare progressive genetic disorder, caused by functional defects in WRN protein and RecQ4L DNA helicase. Acceleration of the aging process is initiated at puberty and the expected life span is approximately the late 50 s. However, a Wrn-deficient mouse model does not show premature aging phenotypes or a short life span, implying that aging processes differ greatly between humans and mice. Gene expression analysis of WRN cells reveals very similar results to gene expression analysis of Hutchinson Gilford progeria syndrome (HGPS) cells, suggesting that these human progeroid syndromes share a common pathological mechanism. Here we show that WRN cells also express progerin, an abnormal variant of the lamin A protein. In addition, we reveal that duplicated sequences of human WRN (hWRN) from exon 9 to exon 10, which differ from the sequence of mouse WRN (mWRN), are a natural inhibitor of progerin. Overexpression of hWRN reduced progerin expression and aging features in HGPS cells. Furthermore, the elimination of progerin by siRNA or a progerin-inhibitor (SLC-D011 also called progerinin) can ameliorate senescence phenotypes in WRN fibroblasts and cardiomyocytes, derived from WRN-iPSCs. These results suggest that progerin, which easily accumulates under WRN-deficient conditions, can lead to premature aging in WRN and that this effect can be prevented by SLC-D011.

scholarly journals Analysis of mitotic and meiotic defects in Saccharomyces cerevisiae SRS2 DNA helicase mutants.

Genetics ◽  
1992 ◽  
Vol 132 (1) ◽  
pp. 23-37 ◽  
Author(s):  
F Palladino ◽  
H L Klein
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Helicase ◽  
Missense Mutations ◽  
Spore Viability ◽  
Mutational Change ◽  
Uv Sensitivity ◽  
Helicase Gene ◽  
Definition Of ◽  
Gene Variability ◽  
New Alleles

Abstract The hyper-gene conversion srs2-101 mutation of the SRS2 DNA helicase gene of Saccharomyces cerevisiae has been reported to suppress the UV sensitivity of rad18 mutants. New alleles of SRS2 were recovered using this suppressor phenotype. The alleles have been characterized with respect to suppression of rad18 UV sensitivity, hyperrecombination, reduction of meiotic viability, and definition of the mutational change within the SRS2 gene. Variability in the degree of rad18 suppression and hyperrecombination were found. The alleles that showed the severest effects were found to be missense mutations within the consensus domains of the DNA helicase family of proteins. The effect of mutations in domains I (ATP-binding) and V (proposed DNA binding) are reported. Some alleles of SRS2 reduce spore viability to 50% of wild-type levels. This phenotype is not bypassed by spo13 mutation. Although the srs2 homozygous diploids strains undergo normal commitment to meiotic recombination, this event is delayed by several hours in the mutant strains and the strains appear to stall in the progression from meiosis I to meiosis II.

scholarly journals DNA Unwinding Is an MCM Complex-dependent and ATP Hydrolysis-dependent Process

2004 ◽  
Vol 279 (44) ◽  
pp. 45586-45593 ◽  
Author(s):  
David Shechter ◽  
Carol Y. Ying ◽  
Jean Gautier
Keyword(s):  
Dna Replication ◽  
Neutralizing Antibodies ◽  
Atp Hydrolysis ◽  
Initial Period ◽  
Dna Helicase ◽  
Dna Unwinding ◽  
Origin Firing ◽  
Replicative Helicase ◽  
Mcm Proteins

Minichromosome maintenance proteins (Mcm) are essential in all eukaryotes and are absolutely required for initiation of DNA replication. The eukaryotic and archaeal Mcm proteins have conserved helicase motifs and exhibit DNA helicase and ATP hydrolysis activitiesin vitro. Although the Mcm proteins have been proposed to be the replicative helicase, the enzyme that melts the DNA helix at the replication fork, their function during cellular DNA replication elongation is still unclear. Using nucleoplasmic extract (NPE) fromXenopus laeviseggs and six purified polyclonal antibodies generated against each of theXenopusMcm proteins, we have demonstrated that Mcm proteins are required during DNA replication and DNA unwinding after initiation of replication. Quantitative depletion of Mcms from the NPE results in normal replication and unwinding, confirming that Mcms are required before pre-replicative complex assembly and dispensable thereafter. Replication and unwinding are inhibited when pooled neutralizing antibodies against the six different Mcm2–7 proteins are added during NPE incubation. Furthermore, replication is blocked by the addition of the Mcm antibodies after an initial period of replication in the NPE, visualized by a pulse of radiolabeled nucleotide at the same time as antibody addition. Addition of the cyclin-dependent kinase 2 inhibitor p21cip1specifically blocks origin firing but does not prevent helicase action. When p21cip1is added, followed by the non-hydrolyzable analog ATPγS to block helicase function, unwinding is inhibited, demonstrating that plasmid unwinding is specifically attributable to an ATP hydrolysis-dependent function. These data support the hypothesis that the Mcm protein complex functions as the replicative helicase.

Understanding Vascular Diseases: Lessons From Premature Aging Syndromes

2016 ◽  
Vol 32 (5) ◽  
pp. 650-658 ◽  
Author(s):  
Yuichi Ikeda ◽  
Hidetoshi Kumagai ◽  
Yoshihiro Motozawa ◽  
Jun-ichi Suzuki ◽  
Hiroshi Akazawa ◽  
...  
Keyword(s):  
Vascular Diseases ◽  
Premature Aging ◽  
Premature Aging Syndromes

Stimulation of DNA Synthesis by Mouse DNA Helicase B in a DNA Replication System Containing Eukaryotic Replication Origins

Biochemistry ◽  
1995 ◽  
Vol 34 (24) ◽  
pp. 7913-7922 ◽  
Author(s):  
Ken Matsumoto ◽  
Masayuki Seki ◽  
Chikahide Masutani ◽  
Shusuke Tada ◽  
Takemi Enomoto ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Synthesis ◽  
Dna Helicase ◽  
Replication Origins ◽  
Replication System ◽  
Stimulation Of

scholarly journals Mutations in the WRN Gene in Mice Accelerate Mortality in a p53-Null Background

2000 ◽  
Vol 20 (9) ◽  
pp. 3286-3291 ◽  
Author(s):  
David B. Lombard ◽  
Caroline Beard ◽  
Brad Johnson ◽  
Robert A. Marciniak ◽  
Jessie Dausman ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Life Span ◽  
Human Disease ◽  
Dna Helicase ◽  
Premature Aging ◽  
Mutant Mice ◽  
Helicase Domain ◽  
C Terminus ◽  
Accelerated Senescence

ABSTRACT Werner's syndrome (WS) is a human disease with manifestations resembling premature aging. The gene defective in WS, WRN, encodes a DNA helicase. Here, we describe the generation of mice bearing a mutation that eliminates expression of the C terminus of the helicase domain of the WRN protein. Mutant mice are born at the expected Mendelian frequency and do not show any overt histological signs of accelerated senescence. These mice are capable of living beyond 2 years of age. Cells from these animals do not show elevated susceptibility to the genotoxins camptothecin or 4-NQO. However, mutant fibroblasts senesce approximately one passage earlier than controls. Importantly,WRN−/− ;p53−/− mice show an increased mortality rate relative toWRN+/− ;p53−/− animals. We consider possible models for the synergy betweenp53 and WRN mutations for the determination of life span.

Aging, cellular senescence and cancer: epigenetic alterations and nuclear remodeling

2019 ◽  
pp. 238-253
Author(s):  
John C. Lucchesi
Keyword(s):  
Histone Modifications ◽  
Cellular Senescence ◽  
Aging Process ◽  
Nuclear Architecture ◽  
Gene Mutations ◽  
Histone Variants ◽  
Premature Aging ◽  
Model Organisms ◽  
Premature Aging Syndromes ◽  
Nuclear Remodeling

Epigenetic modifications correlated with aging and oncogenesis are changes in the pattern of DNA methylation and of histone modifications, and changes in the level of histone variants (H3.3, macroH2A, H2A.Z) and gene mutations. The sirtuins are a set of highly conserved protein deacetylases of particular significance to the aging process. Many cancer types are found to carry mutations in chromatin-modifying genes such as those encoding methyl or acetyl transferases, affecting the histone modifications of promoters and enhancers. The aging process and oncogenesis present a number of changes in the nuclear architecture. Mutations in the lamina-coding genes lead to premature aging syndromes. Mutations in remodeling complexes are found in different cancers. Modifications that affect the architectural protein binding sites at topologically associating domain (TAD) borders can cause the merging of neighboring TADs. The levels of short non-coding RNAs (sncRNAs) are altered in model organisms and are associated with cancer. Changes in the position of chromosome territories often occur in tumor cells. Nevertheless, cellular senescence, due mostly to the absence of telomerase, represents a mechanism of tumor suppression.

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