scholarly journals Mus81-Mms4 endonuclease is an Esc2-STUbL-Cullin8 mitotic substrate impacting on genome integrity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Anja Waizenegger ◽  
Madhusoodanan Urulangodi ◽  
Carl P. Lehmann ◽  
Teresa Anne Clarisse Reyes ◽  
Irene Saugar ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
Genome Stability ◽  
Active State ◽  
Genome Integrity ◽  
Dna Damage Checkpoint ◽  
Proteasome Degradation ◽  
Abnormal Processing

AbstractThe Mus81-Mms4 nuclease is activated in G2/M via Mms4 phosphorylation to allow resolution of persistent recombination structures. However, the fate of the activated phosphorylated Mms4 remains unknown. Here we find that Mms4 is engaged by (poly)SUMOylation and ubiquitylation and targeted for proteasome degradation, a process linked to the previously described Mms4 phosphorylation cycle. Mms4 is a mitotic substrate for the SUMO-Targeted Ubiquitin ligase Slx5/8, the SUMO-like domain-containing protein Esc2, and the Mms1-Cul8 ubiquitin ligase. In the absence of these activities, phosphorylated Mms4 accumulates on chromatin in an active state in the next G1, subsequently causing abnormal processing of replication-associated recombination intermediates and delaying the activation of the DNA damage checkpoint. Mus81-Mms4 mutants that stabilize phosphorylated Mms4 have similar detrimental effects on genome integrity. Overall, our findings highlight a replication protection function for Esc2-STUbL-Cul8 and emphasize the importance for genome stability of resetting phosphorylated Mms4 from one cycle to another.

scholarly journals Monitoring S. pombe genome stress by visualizing end-binding protein Ku

2020 ◽  
Author(s):  
Chance Jones ◽  
Susan L Forsburg
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Protein Complex ◽  
Genome Stability ◽  
Binding Protein ◽  
Dna Lesions ◽  
Live Cells ◽  
Dna Damage Checkpoint ◽  
Unique Pattern ◽  
Ku Protein

AbstractStudies of genome stability have exploited visualization of fluorescently tagged proteins in live cells to characterize DNA damage, checkpoint, and repair responses. In this report, we describe a new tool for fission yeast, a tagged version of the end-binding protein Pku70 which is part of the KU protein complex. We compare Pku70 localization to other markers upon treatment to various genotoxins, and identify a unique pattern of distribution. Pku70 provides a new tool to define and characterize DNA lesions and the repair response.

scholarly journals Genome Maintenance Mechanisms at the Chromatin Level

2021 ◽  
Vol 22 (19) ◽  
pp. 10384
Author(s):  
Hirotomo Takatsuka ◽  
Atsushi Shibata ◽  
Masaaki Umeda
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Genome Stability ◽  
Genotoxic Stress ◽  
Genome Integrity ◽  
Easy Access ◽  
Order Structure ◽  
Chromatin Modifications ◽  
Level Control ◽  
Regulatory Systems

Genome integrity is constantly threatened by internal and external stressors, in both animals and plants. As plants are sessile, a variety of environment stressors can damage their DNA. In the nucleus, DNA twines around histone proteins to form the higher-order structure “chromatin”. Unraveling how chromatin transforms on sensing genotoxic stress is, thus, key to understanding plant strategies to cope with fluctuating environments. In recent years, accumulating evidence in plant research has suggested that chromatin plays a crucial role in protecting DNA from genotoxic stress in three ways: (1) changes in chromatin modifications around damaged sites enhance DNA repair by providing a scaffold and/or easy access to DNA repair machinery; (2) DNA damage triggers genome-wide alterations in chromatin modifications, globally modulating gene expression required for DNA damage response, such as stem cell death, cell-cycle arrest, and an early onset of endoreplication; and (3) condensed chromatin functions as a physical barrier against genotoxic stressors to protect DNA. In this review, we highlight the chromatin-level control of genome stability and compare the regulatory systems in plants and animals to find out unique mechanisms maintaining genome integrity under genotoxic stress.

scholarly journals The Yeast PCNA Unloader Elg1 RFC-Like Complex Plays a Role in Eliciting the DNA Damage Checkpoint

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Soumitra Sau ◽  
Batia Liefshitz ◽  
Martin Kupiec
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cellular Response ◽  
Genome Stability ◽  
Adaptor Proteins ◽  
Nuclear Antigen ◽  
Dna Damage Checkpoint ◽  
Activation Process ◽  
Checkpoint Activation ◽  
Dna Replication And Repair

ABSTRACT The PCNA (proliferating cell nuclear antigen) ring plays central roles during DNA replication and repair. The yeast Elg1 RFC-like complex (RLC) is the principal unloader of chromatin-bound PCNA and thus plays a central role in maintaining genome stability. Here we identify a role for Elg1 in the unloading of PCNA during DNA damage. Using DNA damage checkpoint (DC)-inducible and replication checkpoint (RC)-inducible strains, we show that Elg1 is essential for eliciting the signal in the DC branch. In the absence of Elg1 activity, the Rad9 (53BP1) and Dpb11 (TopBP1) adaptor proteins are recruited but fail to be phosphorylated by Mec1 (ATR), resulting in a lack of checkpoint activation. The chromatin immunoprecipitation of PCNA at the Lac operator sites reveals that accumulated local PCNA influences the checkpoint activation process in elg1 mutants. Our data suggest that Elg1 participates in a mechanism that may coordinate PCNA unloading during DNA repair with DNA damage checkpoint induction. IMPORTANCE The Elg1protein forms an RFC-like complex in charge of unloading PCNA from chromatin during DNA replication and repair. Mutations in the ELG1 gene caused genomic instability in all organisms tested and cancer in mammals. Here we show that Elg1 plays a role in the induction of the DNA damage checkpoint, a cellular response to DNA damage. We show that this defect is due to a defect in the signal amplification process during induction. Thus, cells coordinate the cell's response and the PCNA unloading through the activity of Elg1.

scholarly journals The Fission Yeast Crb2/Chk1 Pathway Coordinates the DNA Damage and Spindle Checkpoint in Response to Replication Stress Induced by Topoisomerase I Inhibitor

2005 ◽  
Vol 25 (17) ◽  
pp. 7889-7899 ◽  
Author(s):  
Ada Collura ◽  
Joel Blaisonneau ◽  
Giuseppe Baldacci ◽  
Stefania Francesconi
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Topoisomerase I ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Genetic Material ◽  
Spindle Checkpoint ◽  
Dna Damage Checkpoint ◽  
Replicative Stress

ABSTRACT Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase I, the Chk1 DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G2/M DNA damage checkpoint.

scholarly journals Delineation of the role of chromatin assembly and the Rtt101Mms1 E3 ubiquitin ligase in DNA damage checkpoint recovery in budding yeast

PLoS ONE ◽  
2017 ◽  
Vol 12 (7) ◽  
pp. e0180556 ◽  
Author(s):  
Li-Ting Diao ◽  
Chin-Chuan Chen ◽  
Briana Dennehey ◽  
Sangita Pal ◽  
Pingping Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ubiquitin Ligase ◽  
Budding Yeast ◽  
E3 Ubiquitin Ligase ◽  
Chromatin Assembly ◽  
Dna Damage Checkpoint ◽  
Checkpoint Recovery

scholarly journals Caenorhabditis elegans HUS-1 Is a DNA Damage Checkpoint Protein Required for Genome Stability and EGL-1-Mediated Apoptosis

2002 ◽  
Vol 12 (22) ◽  
pp. 1908-1918 ◽  
Author(s):  
E.Randal Hofmann ◽  
Stuart Milstein ◽  
Simon J. Boulton ◽  
Mianjia Ye ◽  
Jen J. Hofmann ◽  
...  
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Genome Stability ◽  
Dna Damage Checkpoint ◽  
Checkpoint Protein

scholarly journals N6-Methyladenosine, DNA Repair, and Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Qu ◽  
Pawlos S. Tsegay ◽  
Yuan Liu
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Genome Stability ◽  
Fine Tuning ◽  
Genome Integrity ◽  
Cell Renewal ◽  
The Novel ◽  
Cellular Sensitivity

N6-methyladenosine (m6A) modification in mRNAs and non-coding RNAs is a newly identified epitranscriptomic mark. It provides a fine-tuning of gene expression to serve as a cellular response to endogenous and exogenous stimuli. m6A is involved in regulating genes in multiple cellular pathways and functions, including circadian rhythm, cell renewal, differentiation, neurogenesis, immunity, among others. Disruption of m6A regulation is associated with cancer, obesity, and immune diseases. Recent studies have shown that m6A can be induced by oxidative stress and DNA damage to regulate DNA repair. Also, deficiency of the m6A eraser, fat mass obesity-associated protein (FTO) can increase cellular sensitivity to genotoxicants. These findings shed light on the novel roles of m6A in modulating DNA repair and genome integrity and stability through responding to DNA damage. In this mini-review, we discuss recent progress in the understanding of a unique role of m6As in mRNAs, lncRNAs, and microRNAs in DNA damage response and regulation of DNA repair and genome integrity and instability.

scholarly journals Adaptation to DNA damage as a bet-hedging mechanism in a fluctuating environment

2021 ◽  
Author(s):  
Pierre Roux ◽  
Delphine Salort ◽  
Zhou Xu
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Cell Survival ◽  
Genome Instability ◽  
Population Level ◽  
Signalling Pathway ◽  
Genome Integrity ◽  
Dna Damage Checkpoint ◽  
Bet Hedging

AbstractIn response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared to repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection through-out evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.

scholarly journals Adaptation to DNA damage as a bet-hedging mechanism in a fluctuating environment

2021 ◽  
Vol 8 (8) ◽  
pp. 210460
Author(s):  
Pierre Roux ◽  
Delphine Salort ◽  
Zhou Xu
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Cell Survival ◽  
Genome Instability ◽  
Population Level ◽  
Signalling Pathway ◽  
Genome Integrity ◽  
Dna Damage Checkpoint ◽  
Bet Hedging

In response to DNA damage, efficient repair is essential for cell survival and genome integrity. In eukaryotes, the DNA damage checkpoint is a signalling pathway that coordinates this response and arrests the cell cycle to provide time for repair. However, when repair fails or when the damage is not repairable, cells can eventually bypass the DNA damage checkpoint and undergo cell division despite persistent damage, a process called adaptation to DNA damage. Interestingly, adaptation occurs with a delayed timing compared with repair and shows a large variation in time, two properties that may provide a survival advantage at the population level without interfering with repair. Here, we explore this idea by mathematically modelling cell survival in response to DNA damage and focusing on adaptation parameters. We find that the delayed adaptation timing indeed maximizes survival, but its heterogeneity is beneficial only in a fluctuating damage-inducing environment. Finally, we show that adaptation does not only contribute to survival but also to genome instability and mutations, which might represent another criterion for its selection throughout evolution. Overall, we propose that adaptation can act as a bet-hedging mechanism for cell survival in response to DNA damage.

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