scholarly journals Safeguarding genome integrity: the checkpoint kinases ATR, CHK1 and WEE1 restrain CDK activity during normal DNA replication

2011 ◽  
Vol 40 (2) ◽  
pp. 477-486 ◽  
Author(s):  
C. S. Sorensen ◽  
R. G. Syljuasen
Keyword(s):  
Dna Replication ◽  
Genome Integrity ◽  
Checkpoint Kinases

The MCM helicase: linking checkpoints to the replication fork

2008 ◽  
Vol 36 (1) ◽  
pp. 114-119 ◽  
Author(s):  
Susan L. Forsburg
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Genome Integrity ◽  
Minichromosome Maintenance ◽  
Replication Checkpoint ◽  
Checkpoint Kinases ◽  
Mcm Helicase ◽  
Mcm Proteins

The MCM (minichromosome maintenance) complex is a helicase which is essential for DNA replication. Recent results suggest that the MCM helicase is important for replication fork integrity, and may function as a target of the replication checkpoint. Interactions between MCM proteins, checkpoint kinases, and repair and recovery proteins suggest that MCMs are proximal effectors of replication fork stability in the cell and are likely to play an important role in maintaining genome integrity.

scholarly journals Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
André Franz ◽  
Paul A. Pirson ◽  
Domenic Pilger ◽  
Swagata Halder ◽  
Divya Achuthankutty ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dynamic Process ◽  
Metabolic Pathways ◽  
Replication Fork ◽  
Genome Instability ◽  
Genome Integrity ◽  
Substrate Selection ◽  
Replication Fork Progression ◽  
Replication Factors ◽  
Spatiotemporal Control

Abstract The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.

scholarly journals DNA replication and spindle checkpoints cooperate during S phase to delay mitosis and preserve genome integrity

2014 ◽  
Vol 204 (2) ◽  
pp. 165-175 ◽  
Author(s):  
Maria M. Magiera ◽  
Elisabeth Gueydon ◽  
Etienne Schwob
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Stress ◽  
S Phase ◽  
Genome Integrity ◽  
Replication Forks ◽  
Mitotic Entry ◽  
Transient Activation ◽  
Spindle Checkpoints ◽  
Spindle Assembly Checkpoints

Deoxyribonucleic acid (DNA) replication and chromosome segregation must occur in ordered sequence to maintain genome integrity during cell proliferation. Checkpoint mechanisms delay mitosis when DNA is damaged or upon replication stress, but little is known on the coupling of S and M phases in unperturbed conditions. To address this issue, we postponed replication onset in budding yeast so that DNA synthesis is still underway when cells should enter mitosis. This delayed mitotic entry and progression by transient activation of the S phase, G2/M, and spindle assembly checkpoints. Disabling both Mec1/ATR- and Mad2-dependent controls caused lethality in cells with deferred S phase, accompanied by Rad52 foci and chromosome missegregation. Thus, in contrast to acute replication stress that triggers a sustained Mec1/ATR response, multiple pathways cooperate to restrain mitosis transiently when replication forks progress unhindered. We suggest that these surveillance mechanisms arose when both S and M phases were coincidently set into motion by a unique ancestral cyclin–Cdk1 complex.

scholarly journals Response of Xenopus Cds1 in Cell-free Extracts to DNA Templates with Double-stranded Ends

2000 ◽  
Vol 11 (5) ◽  
pp. 1535-1546 ◽  
Author(s):  
Zijian Guo ◽  
William G. Dunphy
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Dna Molecules ◽  
Dna Templates ◽  
Cell Cycle Delay ◽  
Checkpoint Kinases ◽  
Double Stranded Dna ◽  
Egg Extracts ◽  
Dna Ends ◽  
Damaged Dna

Although homologues of the yeast checkpoint kinases Cds1 and Chk1 have been identified in various systems, the respective roles of these kinases in the responses to damaged and/or unreplicated DNA in vertebrates have not been delineated precisely. Likewise, it is largely unknown how damaged DNA and unreplicated DNA trigger the pathways that contain these effector kinases. We report that XenopusCds1 (Xcds1) is phosphorylated and activated by the presence of some simple DNA molecules with double-stranded ends in cell-freeXenopus egg extracts. Xcds1 is not affected by aphidicolin, an agent that induces DNA replication blocks. In contrast,Xenopus Chk1 (Xchk1) responds to DNA replication blocks but not to the presence of double-stranded DNA ends. Immunodepletion of Xcds1 (and/or Xchk1) from egg extracts did not attenuate the cell cycle delay induced by double-stranded DNA ends. These results imply that the cell cycle delay triggered by double-stranded DNA ends either does not involve Xcds1 or uses a factor(s) that can act redundantly with Xcds1.

scholarly journals Archaeal Genome Guardians Give Insights into Eukaryotic DNA Replication and Damage Response Proteins

Archaea ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-24 ◽  
Author(s):  
David S. Shin ◽  
Ashley J. Pratt ◽  
John A. Tainer
Keyword(s):  
Dna Replication ◽  
Environmental Stress ◽  
Stress Responses ◽  
Protein Structures ◽  
Genome Integrity ◽  
Damage Response ◽  
Dna Replication And Repair ◽  
The Face ◽  
Domains Of Life ◽  
Fundamental Systems

As the third domain of life, archaea, like the eukarya and bacteria, must have robust DNA replication and repair complexes to ensure genome fidelity. Archaea moreover display a breadth of unique habitats and characteristics, and structural biologists increasingly appreciate these features. As archaea include extremophiles that can withstand diverse environmental stresses, they provide fundamental systems for understanding enzymes and pathways critical to genome integrity and stress responses. Such archaeal extremophiles provide critical data on the periodic table for life as well as on the biochemical, geochemical, and physical limitations to adaptive strategies allowing organisms to thrive under environmental stress relevant to determining the boundaries for life as we know it. Specifically, archaeal enzyme structures have informed the architecture and mechanisms of key DNA repair proteins and complexes. With added abilities to temperature-trap flexible complexes and reveal core domains of transient and dynamic complexes, these structures provide insights into mechanisms of maintaining genome integrity despite extreme environmental stress. The DNA damage response protein structures noted in this review therefore inform the basis for genome integrity in the face of environmental stress, with implications for all domains of life as well as for biomanufacturing, astrobiology, and medicine.

scholarly journals The yeast core spliceosome maintains genome integrity through R-loop prevention and α-tubulin expression

2018 ◽  
Author(s):  
Annie S. Tam ◽  
Veena Mathew ◽  
Tianna S. Sihota ◽  
Anni Zhang ◽  
Peter C. Stirling
Keyword(s):  
Gene Expression ◽  
Dna Replication ◽  
Chromosome Segregation ◽  
Genome Stability ◽  
Spindle Assembly Checkpoint ◽  
Genome Instability ◽  
Genome Integrity ◽  
Genome Maintenance ◽  
Maintenance Factors ◽  
Spindle Assembly Checkpoint Protein

To achieve genome stability cells must coordinate the action of various DNA transactions including DNA replication, repair, transcription and chromosome segregation. How transcription and RNA processing enable genome stability is only partly understood. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in a panel yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability. Genome instability in splicing mutants is exacerbated by loss of the spindle-assembly checkpoint protein Mad1. Moreover, removal of the intron from the α-tubulin gene TUB1 restores genome integrity. Thus, while R-loops contribute in some settings, defects in yeast splicing predominantly lead to genome instability through effects on gene expression.

scholarly journals MCMBP maintains genome integrity by protecting the MCM subunits from degradation

2019 ◽  
Author(s):  
Venny Santosa ◽  
Masato T. Kanemaki
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Transcriptional Activation ◽  
Damage Accumulation ◽  
Nuclear Protein ◽  
De Novo ◽  
Genome Integrity ◽  
De Novo Synthesis ◽  
Eukaryotic Dna ◽  
High Level

AbstractThe hetero-hexameric MCM2–7 helicase plays a central role in eukaryotic DNA replication. The expression of MCM2–7 is maintained at a high level for creating dormant origins, which are important for maintaining genome integrity. However, other than transcriptional activation for the de novo synthesis, little is known about how cells maintain a high level of MCM2–7. We show that human MCMBP is a short-lived nuclear protein associating mainly with MCM5, 6, and 7. Loss of MCMBP down-regulates MCM2–7, leading to replication stress and DNA-damage accumulation. Our work demonstrates MCMBP protects the MCM subunits from degradation and suggests its chaperone-like role to achieve a high level of functional MCM2–7 using the nascent and recycled subunits.

scholarly journals Recql5 Plays an Important Role in DNA Replication and Cell Survival after Camptothecin Treatment

2009 ◽  
Vol 20 (1) ◽  
pp. 114-123 ◽  
Author(s):  
Yiduo Hu ◽  
Xincheng Lu ◽  
Guangjin Zhou ◽  
Ellen L. Barnes ◽  
Guangbin Luo
Keyword(s):  
Cell Death ◽  
Dna Replication ◽  
Cell Survival ◽  
Topoisomerase I ◽  
Cancer Susceptibility ◽  
Es Cells ◽  
Genome Integrity ◽  
Mouse Es Cells ◽  
Formidable Challenge ◽  
New Findings

Disruption of replication can lead to loss of genome integrity and increase of cancer susceptibility in mammals. Thus, a replication impediment constitutes a formidable challenge to these organisms. Recent studies indicate that homologous recombination (HR) plays an important role in suppressing genome instability and promoting cell survival after exposure to various replication inhibitors, including a topoisomerase I inhibitor, camptothecin (CPT). Here, we report that the deletion of RecQ helicase Recql5 in mouse ES cells and embryonic fibroblast (MEF) cells resulted in a significant increase in CPT sensitivity and a profound reduction in DNA replication after the treatment with CPT, but not other DNA-damaging agents. This CPT-induced cell death is replication dependent and occurs primarily after the cells had exited the first cell cycle after CPT treatment. Furthermore, we show that Recql5 functions nonredundantly with Rad51, a key factor for HR to protect mouse ES cells from CPT-induced cytotoxicity. These new findings strongly suggest that Recql5 plays an important role in maintaining active DNA replication to prevent the collapse of replication forks and the accumulation of DSBs in order to preserve genome integrity and to prevent cell death after replication stress as a result of topoisomerase I poisoning.

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