scholarly journals Checkpoint silencing during the DNA damage response in Caenorhabditis elegans embryos

2006 ◽  
Vol 172 (7) ◽  
pp. 999-1008 ◽  
Author(s):  
Antonia H. Holway ◽  
Seung-Hwan Kim ◽  
Adriana La Volpe ◽  
W. Matthew Michael
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Replication Fork ◽  
Germ Line ◽  
Checkpoint Activation ◽  
Checkpoint Response ◽  
Damage Response ◽  
Fork Stalling

In most cells, the DNA damage checkpoint delays cell division when replication is stalled by DNA damage. In early Caenorhabditis elegans embryos, however, the checkpoint responds to developmental signals that control the timing of cell division, and checkpoint activation by nondevelopmental inputs disrupts cell cycle timing and causes embryonic lethality. Given this sensitivity to inappropriate checkpoint activation, we were interested in how embryos respond to DNA damage. We demonstrate that the checkpoint response to DNA damage is actively silenced in embryos but not in the germ line. Silencing requires rad-2, gei-17, and the polh-1 translesion DNA polymerase, which suppress replication fork stalling and thereby eliminate the checkpoint-activating signal. These results explain how checkpoint activation is restricted to developmental signals during embryogenesis and insulated from DNA damage. They also show that checkpoint activation is not an obligatory response to DNA damage and that pathways exist to bypass the checkpoint when survival depends on uninterrupted progression through the cell cycle.

scholarly journals Zfp423/ZNF423regulates cell cycle progression, the mode of cell division and the DNA-damage response in Purkinje neuron progenitors

Development ◽  
2017 ◽  
Vol 144 (20) ◽  
pp. 3686-3697 ◽  
Author(s):  
Filippo Casoni ◽  
Laura Croci ◽  
Camilla Bosone ◽  
Roberta D'Ambrosio ◽  
Aurora Badaloni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Damage Response ◽  
Cell Cycle Progression ◽  
Purkinje Neuron ◽  
Cycle Progression ◽  
Damage Response

scholarly journals DNA Damage Response Checkpoint Activation Drives KP1019 Dependent Pre-Anaphase Cell Cycle Delay in S. cerevisiae

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0138085 ◽  
Author(s):  
Lindsey A. Bierle ◽  
Kira L. Reich ◽  
Braden E. Taylor ◽  
Eliot B. Blatt ◽  
Sydney M. Middleton ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Checkpoint Activation ◽  
Cell Cycle Delay ◽  
Damage Response

Succinylation at a key residue of FEN1 is involved in the DNA damage response to maintain genome stability

2020 ◽  
Vol 319 (4) ◽  
pp. C657-C666
Author(s):  
Rongyi Shi ◽  
Yiyi Wang ◽  
Ya Gao ◽  
Xiaoli Xu ◽  
Shuyu Mao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Genome Stability ◽  
Damage Response ◽  
Dna Replication And Repair ◽  
Fork Stalling ◽  
Stalled Replication Forks ◽  
Maintain Genome Stability

Human flap endonuclease 1 (FEN1) is a structure-specific, multifunctional endonuclease essential for DNA replication and repair. Our previous study showed that in response to DNA damage, FEN1 interacts with the PCNA-like Rad9-Rad1-Hus1 complex instead of PCNA to engage in DNA repair activities, such as stalled DNA replication fork repair, and undergoes SUMOylation by SUMO-1. Here, we report that succinylation of FEN1 was stimulated in response to DNA replication fork-stalling agents, such as ultraviolet (UV) irradiation, hydroxyurea, camptothecin, and mitomycin C. K200 is a key succinylation site of FEN1 that is essential for gap endonuclease activity and could be suppressed by methylation and stimulated by phosphorylation to promote SUMO-1 modification. Succinylation at K200 of FEN1 promoted the interaction of FEN1 with the Rad9-Rad1-Hus1 complex to rescue stalled replication forks. Impairment of FEN1 succinylation led to the accumulation of DNA damage and heightened sensitivity to fork-stalling agents. Altogether, our findings suggest an important role of FEN1 succinylation in regulating its roles in DNA replication and repair, thus maintaining genome stability.

scholarly journals MRX-dependent DNA Damage Response to Short Telomeres

2007 ◽  
Vol 18 (8) ◽  
pp. 3047-3058 ◽  
Author(s):  
Valeria Viscardi ◽  
Diego Bonetti ◽  
Hugo Cartagena-Lirola ◽  
Giovanna Lucchini ◽  
Maria Pia Longhese
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Time Window ◽  
Base Pairs ◽  
Checkpoint Activation ◽  
Checkpoint Response ◽  
Strand Breaks ◽  
Telomere Elongation ◽  
Damage Response ◽  
Equilibrium Length

Telomere structure allows cells to distinguish the natural chromosome ends from double-strand breaks (DSBs). However, DNA damage response proteins are intimately involved in telomere metabolism, suggesting that functional telomeres may be recognized as DNA damage during a time window. Here we show by two different systems that short telomeres are recognized as DSBs during the time of their replication, because they induce a transient MRX-dependent DNA damage checkpoint response during their prolonged elongation. The MRX complex, which is recruited at telomeres under these conditions, dissociates from telomeres concomitantly with checkpoint switch off when telomeres reach a new equilibrium length. We also show that MRX recruitment to telomeres is sufficient to activate the checkpoint independently of telomere elongation. We propose that MRX can signal checkpoint activation by binding to short telomeres only when they become competent for elongation. Because full-length telomeres are refractory to MRX binding and the shortest telomeres are elongated of only a few base pairs per generation, this limitation may prevent unscheduled checkpoint activation during an unperturbed S phase.

scholarly journals TRIP13PCH-2 promotes Mad2 localization to unattached kinetochores in the spindle checkpoint response

2015 ◽  
Vol 211 (3) ◽  
pp. 503-516 ◽  
Author(s):  
Christian R. Nelson ◽  
Tom Hwang ◽  
Pin-Hsi Chen ◽  
Needhi Bhalla
Keyword(s):  
Cell Division ◽  
Caenorhabditis Elegans ◽  
Spindle Checkpoint ◽  
Checkpoint Activation ◽  
Checkpoint Signaling ◽  
Checkpoint Response ◽  
Aaa Atpase ◽  
C Elegans ◽  
Anaphase Onset ◽  
Data Support

The spindle checkpoint acts during cell division to prevent aneuploidy, a hallmark of cancer. During checkpoint activation, Mad1 recruits Mad2 to kinetochores to generate a signal that delays anaphase onset. Yet, whether additional factors contribute to Mad2’s kinetochore localization remains unclear. Here, we report that the conserved AAA+ ATPase TRIP13PCH-2 localizes to unattached kinetochores and is required for spindle checkpoint activation in Caenorhabditis elegans. pch-2 mutants effectively localized Mad1 to unattached kinetochores, but Mad2 recruitment was significantly reduced. Furthermore, we show that the C. elegans orthologue of the Mad2 inhibitor p31(comet)CMT-1 interacts with TRIP13PCH-2 and is required for its localization to unattached kinetochores. These factors also genetically interact, as loss of p31(comet)CMT-1 partially suppressed the requirement for TRIP13PCH-2 in Mad2 localization and spindle checkpoint signaling. These data support a model in which the ability of TRIP13PCH-2 to disassemble a p31(comet)/Mad2 complex, which has been well characterized in the context of checkpoint silencing, is also critical for spindle checkpoint activation.

scholarly journals Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

2019 ◽  
Vol 202 (2) ◽  
Author(s):  
Peter E. Burby ◽  
Lyle A. Simmons
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Division ◽  
Dna Replication ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Sos Response ◽  
Bacterial Cells ◽  
Cycle Progression ◽  
Content Type

ABSTRACT All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

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