scholarly journals Damage and Replication Stress Responses

10.5772/21986 ◽  
2011 ◽  
Author(s):  
Haiying Wang ◽  
Ping Shen ◽  
Wei-Guo Zhu
Keyword(s):  
Stress Responses ◽  
Replication Stress

scholarly journals Detours to Replication: Functions of Specialized DNA Polymerases during Oncogene-induced Replication Stress

2018 ◽  
Vol 19 (10) ◽  
pp. 3255 ◽  
Author(s):  
Wei-Chung Tsao ◽  
Kristin Eckert
Keyword(s):  
Dna Replication ◽  
Stress Responses ◽  
Dna Polymerases ◽  
Repetitive Sequences ◽  
Replication Stress ◽  
Fragile Sites ◽  
Cancer Development ◽  
Cycle Arrest ◽  
Chromosomal Fragile Sites ◽  
Dna Secondary Structures

Incomplete and low-fidelity genome duplication contribute to genomic instability and cancer development. Difficult-to-Replicate Sequences, or DiToRS, are natural impediments in the genome that require specialized DNA polymerases and repair pathways to complete and maintain faithful DNA synthesis. DiToRS include non B-DNA secondary structures formed by repetitive sequences, for example within chromosomal fragile sites and telomeres, which inhibit DNA replication under endogenous stress conditions. Oncogene activation alters DNA replication dynamics and creates oncogenic replication stress, resulting in persistent activation of the DNA damage and replication stress responses, cell cycle arrest, and cell death. The response to oncogenic replication stress is highly complex and must be tightly regulated to prevent mutations and tumorigenesis. In this review, we summarize types of known DiToRS and the experimental evidence supporting replication inhibition, with a focus on the specialized DNA polymerases utilized to cope with these obstacles. In addition, we discuss different causes of oncogenic replication stress and its impact on DiToRS stability. We highlight recent findings regarding the regulation of DNA polymerases during oncogenic replication stress and the implications for cancer development.

scholarly journals Transcriptome Analysis of Escherichia coli during dGTP Starvation

2016 ◽  
Vol 198 (11) ◽  
pp. 1631-1644 ◽  
Author(s):  
Mark Itsko ◽  
Roel M. Schaaper
Keyword(s):  
Escherichia Coli ◽  
Dna Replication ◽  
Stress Responses ◽  
De Novo ◽  
Replication Stress ◽  
Building Blocks ◽  
Content Type ◽  
Final Cause ◽  
E Coli ◽  
Genome Wide

ABSTRACTOur laboratory recently discovered thatEscherichia colicells starved for the DNA precursor dGTP are killed efficiently (dGTP starvation) in a manner similar to that described for thymineless death (TLD). Conditions for specific dGTP starvation can be achieved by depriving anE. colioptA1 gptstrain of the purine nucleotide precursor hypoxanthine (Hx). To gain insight into the mechanisms underlying dGTP starvation, we conducted genome-wide gene expression analyses of actively growingoptA1 gptcells subjected to hypoxanthine deprivation for increasing periods. The data show that upon Hx withdrawal, theoptA1 gptstrain displays a diminished ability to derepress thede novopurine biosynthesis genes, likely due to internal guanine accumulation. The impairment in fully inducing thepurRregulon may be a contributing factor to the lethality of dGTP starvation. At later time points, and coinciding with cell lethality, strong induction of the SOS response was observed, supporting the concept of replication stress as a final cause of death. No evidence was observed in the starved cells for the participation of other stress responses, including therpoS-mediated global stress response, reinforcing the lack of feedback of replication stress to the global metabolism of the cell. The genome-wide expression data also provide direct evidence for increased genome complexity during dGTP starvation, as a markedly increased gradient was observed for expression of genes located near the replication origin relative to those located toward the replication terminus.IMPORTANCEControl of the supply of the building blocks (deoxynucleoside triphosphates [dNTPs]) for DNA replication is important for ensuring genome integrity and cell viability. When cells are starved specifically for one of the four dNTPs, dGTP, the process of DNA replication is disturbed in a manner that can lead to eventual death. In the present study, we investigated the transcriptional changes in the bacteriumE. coliduring dGTP starvation. The results show increasing DNA replication stress with an increased time of starvation, as evidenced by induction of the bacterial SOS system, as well as a notable lack of induction of other stress responses that could have saved the cells from cell death by slowing down cell growth.

scholarly journals Histone dynamics during DNA replication stress

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Chia-Ling Hsu ◽  
Shin Yen Chong ◽  
Chia-Yeh Lin ◽  
Cheng-Fu Kao
Keyword(s):  
Stress Responses ◽  
Genome Stability ◽  
Genome Instability ◽  
Replication Stress ◽  
Dna Lesions ◽  
Protective Mechanisms ◽  
Replication Process ◽  
Dna Replication Stress ◽  
External Sources

AbstractAccurate and complete replication of the genome is essential not only for genome stability but also for cell viability. However, cells face constant threats to the replication process, such as spontaneous DNA modifications and DNA lesions from endogenous and external sources. Any obstacle that slows down replication forks or perturbs replication dynamics is generally considered to be a form of replication stress, and the past decade has seen numerous advances in our understanding of how cells respond to and resolve such challenges. Furthermore, recent studies have also uncovered links between defects in replication stress responses and genome instability or various diseases, such as cancer. Because replication stress takes place in the context of chromatin, histone dynamics play key roles in modulating fork progression and replication stress responses. Here, we summarize the current understanding of histone dynamics in replication stress, highlighting recent advances in the characterization of fork-protective mechanisms.

scholarly journals Distinct roles of structure-specific endonucleases EEPD1 and Metnase in replication stress responses

NAR Cancer ◽  
2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Neelam Sharma ◽  
Michael C Speed ◽  
Christopher P Allen ◽  
David G Maranon ◽  
Elizabeth Williamson ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Cell Lines ◽  
Stress Responses ◽  
Genome Instability ◽  
Replication Stress ◽  
Cancer Etiology ◽  
Double Knockout ◽  
Damage Response ◽  
Stalled Replication Forks ◽  
Single Knockout

Abstract Accurate DNA replication and segregation are critical for maintaining genome integrity and suppressing cancer. Metnase and EEPD1 are DNA damage response (DDR) proteins frequently dysregulated in cancer and implicated in cancer etiology and tumor response to genotoxic chemo- and radiotherapy. Here, we examine the DDR in human cell lines with CRISPR/Cas9 knockout of Metnase or EEPD1. The knockout cell lines exhibit slightly slower growth rates, significant hypersensitivity to replication stress, increased genome instability and distinct alterations in DDR signaling. Metnase and EEPD1 are structure-specific nucleases. EEPD1 is recruited to and cleaves stalled forks to initiate fork restart by homologous recombination. Here, we demonstrate that Metnase is also recruited to stalled forks where it appears to dimethylate histone H3 lysine 36 (H3K36me2), raising the possibility that H3K36me2 promotes DDR factor recruitment or limits nucleosome eviction to protect forks from nucleolytic attack. We show that stalled forks are cleaved normally in the absence of Metnase, an important and novel result because a prior study indicated that Metnase nuclease is important for timely fork restart. A double knockout was as sensitive to etoposide as either single knockout, suggesting a degree of epistasis between Metnase and EEPD1. We propose that EEPD1 initiates fork restart by cleaving stalled forks, and that Metnase may promote fork restart by processing homologous recombination intermediates and/or inducing H3K36me2 to recruit DDR factors. By accelerating fork restart, Metnase and EEPD1 reduce the chance that stalled replication forks will adopt toxic or genome-destabilizing structures, preventing genome instability and cancer. Metnase and EEPD1 are overexpressed in some cancers and thus may also promote resistance to genotoxic therapeutics.

A novel WEE1 pathway for replication stress responses

Nature Plants ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. 209-218
Author(s):  
Ting Pan ◽  
Qi Qin ◽  
Chubing Nong ◽  
Shan Gao ◽  
Lili Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Replication Stress

scholarly journals Roles of Claspin in regulation of DNA replication, replication stress responses and oncogenesis in human cells

2021 ◽  
Author(s):  
Hao-Wen Hsiao ◽  
Chi-Chun Yang ◽  
Hisao Masai
Keyword(s):  
Dna Replication ◽  
Stress Responses ◽  
Replication Fork ◽  
Therapeutic Potential ◽  
Genome Instability ◽  
Intramolecular Interaction ◽  
Replication Stress ◽  
Human Cells ◽  
Entire Genome ◽  
Replication Checkpoint

AbstractHuman cells need to cope with the stalling of DNA replication to complete replication of the entire genome to minimize genome instability. They respond to “replication stress” by activating the conserved ATR-Claspin-Chk1 replication checkpoint pathway. The stalled replication fork is detected and stabilized by the checkpoint proteins to prevent disintegration of the replication fork, to remove the lesion or problems that are causing fork block, and to facilitate the continuation of fork progression. Claspin, a factor conserved from yeasts to human, plays a crucial role as a mediator that transmits the replication fork arrest signal from the sensor kinase, ataxia telangiectasia and Rad3-related (ATR), to the effector kinase, Checkpoint kinase 1 (Chk1). Claspin interacts with multiple kinases and replication factors and facilitates efficient replication fork progression and initiation during the normal course of DNA replication as well. It interacts with Cdc7 kinase through the acidic patch segment near the C-terminus and this interaction is critical for efficient phosphorylation of Mcm in non-cancer cells and also for checkpoint activation. Phosphorylation of Claspin by Cdc7, recruited to the acidic patch, regulates the conformation of Claspin through affecting the intramolecular interaction between the N- and C-terminal segments of Claspin. Abundance of Claspin is regulated at both mRNA and protein levels (post-transcriptional regulation and protein stability) and affects the extent of replication checkpoint. In this article, we will discuss how the ATR-Claspin-Chk1 regulates normal and stressed DNA replication and provide insight into the therapeutic potential of targeting replication checkpoint for efficient cancer cell death.

scholarly journals Critical Roles of Ring Finger Protein RNF8 in Replication Stress Responses

2011 ◽  
Vol 286 (25) ◽  
pp. 22355-22361 ◽  
Author(s):  
Shirley M.-H. Sy ◽  
Jun Jiang ◽  
Sui-sui Dong ◽  
Gabriel Tsz Mei Lok ◽  
Jun Wu ◽  
...  
Keyword(s):  
Stress Responses ◽  
Ring Finger ◽  
Replication Stress ◽  
Ring Finger Protein ◽  
Finger Protein

scholarly journals Low-dose DNA damage and replication stress responses quantified by optimized automated single-cell image analysis

Cell Cycle ◽  
2009 ◽  
Vol 8 (16) ◽  
pp. 2592-2599 ◽  
Author(s):  
Martin Mistrik ◽  
Lenka Oplustilova ◽  
Jiri Lukas ◽  
Jiri Bartek
Keyword(s):  
Dna Damage ◽  
Image Analysis ◽  
Single Cell ◽  
Stress Responses ◽  
Low Dose ◽  
Replication Stress ◽  
Cell Image ◽  
Cell Image Analysis

scholarly journals Author Correction: A novel WEE1 pathway for replication stress responses

Nature Plants ◽  
2021 ◽  
Vol 7 (3) ◽  
pp. 376-376
Author(s):  
Ting Pan ◽  
Qi Qin ◽  
Chubing Nong ◽  
Shan Gao ◽  
Lili Wang ◽  
...  
Keyword(s):  
Stress Responses ◽  
Replication Stress

scholarly journals The ATR-WEE1 kinase module inhibits the MAC complex to regulate replication stress response

2021 ◽  
Vol 49 (3) ◽  
pp. 1411-1425 ◽  
Author(s):  
Lili Wang ◽  
Li Zhan ◽  
Yan Zhao ◽  
Yongchi Huang ◽  
Chong Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stress Responses ◽  
Genome Stability ◽  
Intron Retention ◽  
Cell Cycle Control ◽  
Replication Stress ◽  
Loss Of Function ◽  
Evolutionarily Conserved ◽  
Subsequent Degradation ◽  
Wee1 Kinase

Abstract DNA damage response is a fundamental mechanism to maintain genome stability. The ATR-WEE1 kinase module plays a central role in response to replication stress. Although the ATR-WEE1 pathway has been well studied in yeasts and animals, how ATR-WEE1 functions in plants remains unclear. Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. Biochemical studies revealed that WEE1 directly interacts with and phosphorylates PRL1 at Serine 145, which promotes PRL1 ubiquitination and subsequent degradation. In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. Our study discovered PRL1 or the MAC complex as a key downstream regulator of the ATR-WEE1 module and revealed a novel cell cycle control mechanism.

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