scholarly journals The Caenorhabditis elegans RAD-51 isoform A is required for the induction of DNA-damage-dependent apoptosis

2017 ◽  
Author(s):  
Marcello Germoglio ◽  
Adele Adamo
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Genome Stability ◽  
Protein Isoforms ◽  
Late Development ◽  
Checkpoint Activation ◽  
Late Pachytene ◽  
Alternative Protein ◽  
New Finding ◽  
Induced Apoptosis

AbstractThe rad-51 gene in Caenorhabditis elegans is transcribed into alternative mRNAs potentially coding three alternative protein isoforms. We have genetically modified this gene in order to investigate the potential roles of the longest isoform, namely isoform A, in genome stability. The RAD-51 isoform A appears to contribute to genome stability in late development, but is not implicated in meiosis or DNA repair in the germline. However, the RAD-51 isoform A has a pivotal role in DNA damage induced apoptosis, but not in DNA damage checkpoint activation or physiological cell death. This is a relevant new finding that improves our understanding of how DNA damage apoptosis is restricted to late pachytene stage preventing the inappropriate loss of nuclei undergoing the earlier stages of meiotic recombination, during which a large number of physiologically induced DSBs are present.

scholarly journals Eukaryotic clamp loaders and unloaders in the maintenance of genome stability

2020 ◽  
Vol 52 (12) ◽  
pp. 1948-1958
Author(s):  
Kyoo-young Lee ◽  
Su Hyung Park
Keyword(s):  
Dna Damage ◽  
Genomic Instability ◽  
Genome Stability ◽  
Critical Role ◽  
Nuclear Antigen ◽  
Checkpoint Activation ◽  
Sliding Clamp ◽  
Clamp Loaders ◽  
Factor C

AbstractEukaryotic sliding clamp proliferating cell nuclear antigen (PCNA) plays a critical role as a processivity factor for DNA polymerases and as a binding and acting platform for many proteins. The ring-shaped PCNA homotrimer and the DNA damage checkpoint clamp 9-1-1 are loaded onto DNA by clamp loaders. PCNA can be loaded by the pentameric replication factor C (RFC) complex and the CTF18-RFC-like complex (RLC) in vitro. In cells, each complex loads PCNA for different purposes; RFC-loaded PCNA is essential for DNA replication, while CTF18-RLC-loaded PCNA participates in cohesion establishment and checkpoint activation. After completing its tasks, PCNA is unloaded by ATAD5 (Elg1 in yeast)-RLC. The 9-1-1 clamp is loaded at DNA damage sites by RAD17 (Rad24 in yeast)-RLC. All five RFC complex components, but none of the three large subunits of RLC, CTF18, ATAD5, or RAD17, are essential for cell survival; however, deficiency of the three RLC proteins leads to genomic instability. In this review, we describe recent findings that contribute to the understanding of the basic roles of the RFC complex and RLCs and how genomic instability due to deficiency of the three RLCs is linked to the molecular and cellular activity of RLC, particularly focusing on ATAD5 (Elg1).

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 Requirement for the Phospho-H2AX Binding Module of Crb2 in Double-Strand Break Targeting and Checkpoint Activation

2010 ◽  
Vol 30 (19) ◽  
pp. 4722-4731 ◽  
Author(s):  
Steven L. Sanders ◽  
Ahmad R. Arida ◽  
Funita P. Phan
Keyword(s):  
Dna Damage ◽  
Histone Modification ◽  
Genome Stability ◽  
Strand Break ◽  
Binding Activity ◽  
Critical Element ◽  
Checkpoint Control ◽  
Ionizing Irradiation ◽  
Checkpoint Activation ◽  
Damage Response

ABSTRACT Activation of DNA damage checkpoints requires the rapid accumulation of numerous factors to sites of genomic lesions, and deciphering the mechanisms of this targeting is central to our understanding of DNA damage response. Histone modification has recently emerged as a critical element for the correct localization of damage response proteins, and one key player in this context is the fission yeast checkpoint mediator Crb2. Accumulation of Crb2 at ionizing irradiation-induced double-strand breaks (DSBs) requires two distinct histone marks, dimethylated H4 lysine 20 (H4K20me2) and phosphorylated H2AX (pH2AX). A tandem tudor motif in Crb2 directly binds H4K20me2, and this interaction is required for DSB targeting and checkpoint activation. Similarly, pH2AX is required for Crb2 localization to DSBs and checkpoint control. Crb2 can directly bind pH2AX through a pair of C-terminal BRCT repeats, but the functional significance of this binding has been unclear. Here we demonstrate that loss of its pH2AX-binding activity severely impairs the ability of Crb2 to accumulate at ionizing irradiation-induced DSBs, compromises checkpoint signaling, and disrupts checkpoint-mediated cell cycle arrest. These impairments are similar to that reported for abolition of pH2AX or mutation of the H4K20me2-binding tudor motif of Crb2. Intriguingly, a combined ablation of its two histone modification binding modules yields a strikingly additive reduction in Crb2 activity. These observations argue that binding of the Crb2 BRCT repeats to pH2AX is critical for checkpoint activity and provide new insight into the mechanisms of chromatin-mediated genome stability.

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 WITHDRAWN: Caenorhabditis elegans nuclear hormone receptor NHR-14, cooperates with p53/cep-1 to regulate DNA damage-induced apoptosis

Oncotarget ◽  
2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Junling Shen ◽  
Jiaxin Kang ◽  
Zhuang Yao ◽  
Youli Jian ◽  
Yudong Jing ◽  
...  
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Induced Apoptosis

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

Nickel-induced apoptosis and relevant signal transduction pathways in Caenorhabditis elegans

2010 ◽  
Vol 26 (4) ◽  
pp. 249-256 ◽  
Author(s):  
Cai Kezhou ◽  
Ren Chong ◽  
Yu Zengliang
Keyword(s):  
Signal Transduction ◽  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Cell Apoptosis ◽  
Mapk Signaling ◽  
Signaling Cascades ◽  
Signal Pathways ◽  
C Elegans ◽  
Induced Apoptosis

Many investigations have shown that nickel exposure can induce micronuclei generation, inhibit DNA repair and induce cell apoptosis, both in cells and tissues. However, there is a lack of appropriate in vivo animal models to study the underlying mechanisms of nickel-induced apoptosis. The model organism, Caenorhabditis elegans, has been shown to be a good model for investigating many biological processes. In the present study, we detected 0.01 mM nickel induced significantly germline cell apoptosis after treatment for 12 hours, which demonstrated that C. elegans could be a mammalian in vivo substitute model to study the mechanisms of apoptosis. Then gene knockout C. elegans strains were utilized to investigate the relationship between nickel-induced apoptosis and relevant signal pathways, which were involved in DNA damage and repair, apoptosis regulation and damage signal transduction. The results presented here demonstrated that nickel-induced apoptosis was independent of the DNA damage response gene, such as hus-1, p53/cep-1 and egl-1. The loss-of-function of the genes that related to Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases (MAPK) signaling cascades suppressed nickel-induced germline apoptosis, while ERK signaling cascades have no effects on the nickel-induced germline apoptosis.

scholarly journals Caenorhabditis elegans Protein Arginine Methyltransferase PRMT-5 Negatively Regulates DNA Damage-Induced Apoptosis

PLoS Genetics ◽  
2009 ◽  
Vol 5 (6) ◽  
pp. e1000514 ◽  
Author(s):  
Mei Yang ◽  
Jianwei Sun ◽  
Xiaojuan Sun ◽  
Qinfang Shen ◽  
Zhiyang Gao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Protein Arginine Methyltransferase ◽  
Arginine Methyltransferase ◽  
Induced Apoptosis

scholarly journals Functional characterization of Caenorhabditis elegans cbs-2 gene during meiosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Pamela Santonicola ◽  
Marcello Germoglio ◽  
Domenico Scotto d’Abbusco ◽  
Adele Adamo
Keyword(s):  
Dna Damage ◽  
Caenorhabditis Elegans ◽  
Functional Characterization ◽  
Genotoxic Stress ◽  
Phenotypic Characterization ◽  
Chromosome Fragmentation ◽  
C Elegans ◽  
Synaptonemal Complex Formation ◽  
Induced Apoptosis

AbstractCystathionine β-synthase (CBS) is a eukaryotic enzyme that maintains the cellular homocysteine homeostasis and catalyzes the conversion of homocysteine to L-cystathionine and Hydrogen sulfide, via the trans-sulfuration pathway. In Caenorhabditis elegans, two cbs genes are present: cbs-1 functions similarly as to human CBS, and cbs-2, whose roles are instead unknown. In the present study we performed a phenotypic characterization of the cbs-2 mutant. The null cbs-2 mutant is viable, fertile and shows the wild-type complement of six bivalents in most oocyte nuclei, which is indicative of a correct formation of crossover recombination. In absence of synaptonemal complex formation (syp-2 mutant), loss of cbs-2 leads to chromosome fragmentation, suggesting that cbs-2 is essential during inter-sister repair. Interestingly, although proficient in the activation of the DNA damage checkpoint after exposure to genotoxic stress, the cbs-2 mutant is defective in DNA damage-induced apoptosis in meiotic germ cells. These results suggest possible functions for CBS-2 in meiosis, distinct from a role in the trans-sulfuration pathway. We propose that the C. elegans CBS-2 protein is required for both inter-sister repair and execution of DNA damage-induced apoptosis.

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