The 53BP1 Homolog in C. elegans Influences DNA Repair and Promotes Apoptosis in Response to Ionizing Radiation

Ryu, Jin Sun; Kang, Sang Jo; Koo, Hyeon Sook

doi:10.1371/journal.pone.0064028

Cited by 17 publications

(17 citation statements)

References 56 publications

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“…Furthermore, we observed that HSR-9, the C. elegans ortholog of the 53BP1 DNA damage response protein, accumulates on Z2/Z3 chromatin with similar dynamics as RAD-51 foci ( Figure 2D). Previous work has shown that HSR-9 accumulates on chromatin specifically during a DNA damage response (Ryu et al, 2013). On the basis of these data, we conclude that Z2/Z3 experience DNA damage as a function of nutrient-dependent cell-cycle reentry.…”

Section: Resultssupporting

confidence: 67%

Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells

et al. 2015

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Recent findings have identified highly transcribed genes as a source of genome instability; however, the degree to which large-scale shifts in transcriptional activity cause DNA damage was not known. One example of a large-scale shift in transcriptional activity occurs during development, when maternal regulators are destroyed and zygotic genome activation (ZGA) occurs. Here, we show that ZGA triggers widespread chromosome damage in the primordial germ cells of the nematode C. elegans. We show that ZGA-induced DNA damage activates a checkpoint response, the damage is repaired by factors required for inter-sister homologous recombination, and topoisomerase II plays a role in generating the damage. These findings identify ZGA as a source of intrinsic genome instability in the germline and suggest that genome destabilization may be a general consequence of extreme shifts in cellular transcriptional load.

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Section: Resultssupporting

confidence: 67%

Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells

et al. 2015

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“…If the C. elegans BRC-1 / BRD-1 complex biases DSB repair in favor of HR and prevents other DSB repair pathways such as NHEJ, then in smc-5 mutant germ cells, in which HR is impaired, normal BRC-1 / BRD-1 function could end up trapping DSB repair in an unproductive defective pathway. To test the consequences of impaired initiation of NHEJ, we employed a mutant strain for hsr-9 , the C. elegans 53BP1 homolog ( Ryu et al 2013 ). In mammals, 53BP1 antagonizes the function of BRCA1 by promoting initiation of NHEJ while inhibiting HR ( Zimmermann and De Lange 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Loss ofCaenorhabditis elegansBRCA1 Promotes Genome Stability During Replication insmc-5Mutants

et al. 2014

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DNA damage by ultraviolet (UV) light poses a risk for mutagenesis and a potential hindrance for cell cycle progression. Cells cope with UV-induced DNA damage through two general strategies to repair the damaged nucleotides and to promote cell cycle progression in the presence of UV-damaged DNA. Defining the genetic pathways and understanding how they function together to enable effective tolerance to UV remains an important area of research. The structural maintenance of chromosomes (SMC) proteins form distinct complexes that maintain genome stability during chromosome segregation, homologous recombination, and DNA replication. Using a forward genetic screen, we identified two alleles of smc-5 that exacerbate UV sensitivity in Caenorhabditis elegans. Germ cells of smc-5-defective animals show reduced proliferation, sensitivity to perturbed replication, chromatin bridge formation, and accumulation of RAD-51 foci that indicate the activation of homologous recombination at DNA double-strand breaks. Mutations in the translesion synthesis polymerase polh-1 act synergistically with smc-5 mutations in provoking genome instability after UV-induced DNA damage. In contrast, the DNA damage accumulation and sensitivity of smc-5 mutant strains to replication impediments are suppressed by mutations in the C. elegans BRCA1/BARD1 homologs, brc-1 and brd-1. We propose that SMC-5/6 promotes replication fork stability and facilitates recombination-dependent repair when the BRC-1/BRD-1 complex initiates homologous recombination at stalled replication forks. Our data suggest that BRC-1/BRD-1 can both promote and antagonize genome stability depending on whether homologous recombination is initiated during DNA double-strand break repair or during replication stalling.

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“…Likewise in C . elegans , the hypersensitivity of BRCA1 worms to DSBs was rescued by a LIG4 mutation, and that of RAD54 knockdown worms was reversed by 53BP1 or LIG4 mutations [ 26 ]. Similarly, the hypersensitivity of FANCD2 worms and Fanconi anemia patient cells to ICLs was rescued by inhibiting NHEJ [ 13 ].…”

Section: Resultsmentioning

confidence: 99%

A PHF8 Homolog in C. elegans Promotes DNA Repair via Homologous Recombination

et al. 2015

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PHF8 is a JmjC domain-containing histone demethylase, defects in which are associated with X-linked mental retardation. In this study, we examined the roles of two PHF8 homologs, JMJD-1.1 and JMJD-1.2, in the model organism C. elegans in response to DNA damage. A deletion mutation in either of the genes led to hypersensitivity to interstrand DNA crosslinks (ICLs), while only mutation of jmjd-1.1 resulted in hypersensitivity to double-strand DNA breaks (DSBs). In response to ICLs, JMJD-1.1 did not affect the focus formation of FCD-2, a homolog of FANCD2, a key protein in the Fanconi anemia pathway. However, the dynamic behavior of RPA-1 and RAD-51 was affected by the mutation: the accumulations of both proteins at ICLs appeared normal, but their subsequent disappearance was retarded, suggesting that later steps of homologous recombination were defective. Similar changes in the dynamic behavior of RPA-1 and RAD-51 were seen in response to DSBs, supporting a role of JMJD-1.1 in homologous recombination. Such a role was also supported by our finding that the hypersensitivity of jmjd-1.1 worms to ICLs was rescued by knockdown of lig-4, a homolog of Ligase 4 active in nonhomologous end-joining. The hypersensitivity of jmjd-1.1 worms to ICLs was increased by rad-54 knockdown, suggesting that JMJD-1.1 acts in parallel with RAD-54 in modulating chromatin structure. Indeed, the level of histone H3 Lys9 tri-methylation, a marker of heterochromatin, was higher in jmjd-1.1 cells than in wild-type cells. We conclude that the histone demethylase JMJD-1.1 influences homologous recombination either by relaxing heterochromatin structure or by indirectly regulating the expression of multiple genes affecting DNA repair.

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The 53BP1 Homolog in C. elegans Influences DNA Repair and Promotes Apoptosis in Response to Ionizing Radiation

Cited by 17 publications

References 56 publications

Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells

Zygotic Genome Activation Triggers Chromosome Damage and Checkpoint Signaling in C. elegans Primordial Germ Cells

Loss ofCaenorhabditis elegansBRCA1 Promotes Genome Stability During Replication insmc-5Mutants

A PHF8 Homolog in C. elegans Promotes DNA Repair via Homologous Recombination

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