Programmed DNA Breaks Activate the Germline Genome in Caenorhabditis elegans

Wong, Margaret; Belew, Mezmur D.; Kwieraga, Amanda; Nhan, James D.; Michael, W. Matthew

doi:10.1016/j.devcel.2018.07.002

Cited by 25 publications

(45 citation statements)

References 34 publications

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“…In order to fully understand the impact of this activity in vivo and to what extent PRC2 contributes to R-loop formation at PREs, additional experiments will be necessary. interacts with a subunit of PRC1, colocalizes with PcG proteins in the BX-C, and is implicated in PRE-mediated silencing 54 ; transient Topo II induced breaks have been implicated in regulation of transcription and chromatin compaction 55,56 , and could also be used by PRC2. It is also possible that the activity of PRC2 contributes to RNA-DNA strand exchange at DNA breaks where RNA-DNA hybrids have been shown to form 57 and where PRC2 is recruited 58,59 .…”

Section: Discussionmentioning

confidence: 99%

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

et al. 2020

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Polycomb Group (PcG) proteins form memory of transient transcriptional repression that is necessary for development. In Drosophila, DNA elements termed Polycomb Response Elements (PREs) recruit PcG proteins. How PcG activities are targeted to PREs to maintain repressed states only in appropriate developmental contexts has been difficult to elucidate. PcG complexes modify chromatin, but also interact with both RNA and DNA, and RNA is implicated in PcG targeting and function. Here we show that R-loops form at many PREs in Drosophila embryos, and correlate with repressive states. In vitro, both PRC1 and PRC2 can recognize R-loops and open DNA bubbles. Unexpectedly, we find that PRC2 drives formation of RNA-DNA hybrids, the key component of R-loops, from RNA and dsDNA. Our results identify R-loop formation as a feature of Drosophila PREs that can be recognized by PcG complexes, and RNA-DNA strand exchange as a PRC2 activity that could contribute to R-loop formation.

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Section: Discussionmentioning

confidence: 99%

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

et al. 2020

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“…Evidence exists that translesion polymerases are particularly important during this stage (Kim and Michael 2008;Roerink et al 2012). The first cell-cycle in developing germ lines occurs after an extended period of transcriptional quiescence and synchronized transcriptional onset appears particularly challenging for genome integrity (Wong et al 2018;Ou et al 2019). In contrast, germ cells residing in the adult germ line are subject to cell-cycle and apoptosis checkpoints, and take an excess of 10 hours to complete (Gartner et al 2000).…”

Section: Nature Of Germ Cell Divisions and Mutagenesismentioning

confidence: 99%

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

Meier

Volkova

Hong

et al. 2020

Preprint

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Genome integrity is particularly important in germ cells to faithfully preserve genetic information across generations. As yet little is known about the contribution of various DNA repair pathways to prevent mutagenesis. Using the C. elegans model we analyse mutational spectra that arise in wild-type and 61 DNA repair and DNA damage response mutants cultivated over multiple generations. Overall, 44% of lines show >2-fold increased mutagenesis with a broad spectrum of mutational outcomes including changes in single or multiple types of base substitutions induced by defects in base excision or nucleotide excision repair, or elevated levels of 50-400 bp deletions in translesion polymerase mutants rev-3(pol ζ) and polh-1(pol η). Mutational signatures associated with defective homologous recombination fall into two classes: 1) mutants lacking brc-1/BRCA1 or rad-51/RAD51 paralogs show elevated base substitutions, indels and structural variants, while 2) deficiency for MUS-81/MUS81 and SLX-1/SLX1 nucleases, and HIM-6/BLM, HELQ-1/HELQ and RTEL-1/RTEL1 helicases primarily cause structural variants. Genome-wide investigation of mutagenesis patterns identified elevated rates of tandem duplications often associated with inverted repeats in helq-1 mutants, and a unique pattern of 'translocation' events involving homeologous sequences in rip-1 paralog mutants. atm-1/ATM DNA damage checkpoint mutants harboured complex structural variants enriched in subtelomeric regions, and chromosome end-to-end fusions. Finally, while inactivation of the p53-like gene cep-1 did not affect mutagenesis, combined brc-1 cep-1 deficiency displayed increased, locally clustered mutagenesis. In summary, we provide a global view of how DNA repair pathways prevent germ cell mutagenesis. Endogenous mutagenesis can be caused by nucleotide mis-incorporation during replication and by reactive cellular metabolites. Hydrolytic reactions trigger abundant depurination and depyrimidination events, and the deamination of cytosine and 5-methylcytosine (for review (Lindahl and Barnes 2000)). Reactive oxygen species, byproducts of oxidative phosphorylation and oxygen-dependent enzymatic processes, induce 10,000-100,000 DNA lesions per cell per day including base modifications such as 8-oxo-dG, thymine glycol and DNA single-strand breaks (Ames et al. 1993). In addition, enzymatic and non-enzymatic mechanisms lead to base methylations. For instance, 3-methyladenine and 3-methyl-cytosine can lead to mutations by blocking replication and O 6 -methyl-guanine leads to G>A changes (for review (Lindahl and Barnes 2000)). Metabolic byproducts such as reactive aldehydes form DNA adducts that can crosslink bases on two complementary DNA strands generating obstacles to replication and transcription. DNA double-strand breaks (DSBs) are one of the most toxic DNA lesions and arise when the replication fork is stalled by base modifications, repetitive DNA, DNA sequences prone to form tertiary structures, or collision with the transcription machinery (Mehta and Haber 2014). Neverth...

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“…Furthermore, the liganded androgen receptor triggers site‐specific breakpoints at intronic translocation regions to facilitate rapid intra‐ and inter‐chromosomal interactions . DNA breaks are also required for chromatin de‐compaction and to initiate global gene expression during zygotic genome activation in worms . At present, the relevance of transcription‐associated DNA breaks to NER remains obscure.…”

Section: Dna Damage: Linking Ner To Mrna Synthesismentioning

confidence: 99%

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

et al. 2019

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Transcription is a potential threat to genome integrity, and transcription‐associated DNA damage must be repaired for proper messenger RNA (mRNA) synthesis and for cells to transmit their genome intact into progeny. For a wide range of structurally diverse DNA lesions, cells employ the highly conserved nucleotide excision repair (NER) pathway to restore their genome back to its native form. Recent evidence suggests that NER factors function, in addition to the canonical DNA repair mechanism, in processes that facilitate mRNA synthesis or shape the 3D chromatin architecture. Here, these findings are critically discussed and a working model that explains the puzzling clinical heterogeneity of NER syndromes highlighting the relevance of physiological, transcription‐associated DNA damage to mammalian development and disease is proposed.

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Programmed DNA Breaks Activate the Germline Genome in Caenorhabditis elegans

Cited by 25 publications

References 34 publications

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

RNA-DNA strand exchange by the Drosophila Polycomb complex PRC2

Systematic analysis of mutational spectra associated with DNA repair deficiency inC. elegans

Nucleotide Excision Repair and Transcription‐Associated Genome Instability

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