The <i>Caenorhabditis elegans </i><scp>WRN</scp> helicase promotes double‐strand <scp>DNA</scp> break repair by mediating end resection and checkpoint activation

Ryu, Jin Sun; Koo, Hyeon Sook

doi:10.1002/1873-3468.12724

Cited by 9 publications

(6 citation statements)

References 45 publications

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“…Indeed, we found that depletion of WRN helicase abrogated the short oligonucleotides generated by Dna2 (Supplementary Figure S5E, S5F), consistent with the previous finding that Dna2 acts in conjunction with WRN (or BLM) in resection (55,63,98,106). Interestingly, depletion of WRN from the extract also dramatically inhibited the generation of long cleavage products in the presence or in the absence of Dna2 (Supplementary Figure S5E and F), suggesting that WRN is also involved in the CtIP–MRN pathway of resection initiation.…”

Section: Discussionsupporting

confidence: 91%

Dna2 initiates resection at clean DNA double-strand breaks

Paudyal

Yan

et al. 2017

Nucleic Acids Research

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Nucleolytic resection of DNA double-strand breaks (DSBs) is essential for both checkpoint activation and homology-mediated repair; however, the precise mechanism of resection, especially the initiation step, remains incompletely understood. Resection of blocked ends with protein or chemical adducts is believed to be initiated by the MRN complex in conjunction with CtIP through internal cleavage of the 5′ strand DNA. However, it is not clear whether resection of clean DSBs with free ends is also initiated by the same mechanism. Using the Xenopus nuclear extract system, here we show that the Dna2 nuclease directly initiates the resection of clean DSBs by cleaving the 5′ strand DNA ∼10–20 nucleotides away from the ends. In the absence of Dna2, MRN together with CtIP mediate an alternative resection initiation pathway where the nuclease activity of MRN apparently directly cleaves the 5′ strand DNA at more distal sites. MRN also facilitates resection initiation by promoting the recruitment of Dna2 and CtIP to the DNA substrate. The ssDNA-binding protein RPA promotes both Dna2- and CtIP–MRN-dependent resection initiation, but a RPA mutant can distinguish between these pathways. Our results strongly suggest that resection of blocked and clean DSBs is initiated via distinct mechanisms.

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Section: Discussionsupporting

confidence: 91%

Dna2 initiates resection at clean DNA double-strand breaks

Paudyal

Yan

et al. 2017

Nucleic Acids Research

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“…We started with a C. elegans model of WS, wrn-1(gk99) , which has a 196-bp deletion mutation resulting in the complete absence of the WRN-1 protein 26,27 . This strain recapitulates major features of WS patients, including impaired DSBR, progeroid tissue phenotypes, and shorter lifespan 3,27,28 . Similar to the observations in human WS cells, we found reduced mitochondrial network complexity (42% reduction, Fig.…”

Section: Resultsmentioning

confidence: 80%

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

et al. 2019

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Metabolic dysfunction is a primary feature of Werner syndrome (WS), a human premature aging disease caused by mutations in the gene encoding the Werner (WRN) DNA helicase. WS patients exhibit severe metabolic phenotypes, but the underlying mechanisms are not understood, and whether the metabolic deficit can be targeted for therapeutic intervention has not been determined. Here we report impaired mitophagy and depletion of NAD+, a fundamental ubiquitous molecule, in WS patient samples and WS invertebrate models. WRN regulates transcription of a key NAD+ biosynthetic enzyme nicotinamide nucleotide adenylyltransferase 1 (NMNAT1). NAD+ repletion restores NAD+ metabolic profiles and improves mitochondrial quality through DCT-1 and ULK-1-dependent mitophagy. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

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“…We identified 20 copies of G2E3 in the YHSC genome, compared with three at most in all other genomes examined ( Figure 4 E). WRN , a member of the RecQ family, is a checkpoint protein in the replication fork recovery and double-strand DNA break repair pathway with ATP-dependent 3′-5′ DNA helicase activity 72 , 77 , 93 ( Figures 4 A and 4C). Far more copies of WRN were identified in the YHSC genome than in any other genome examined ( Figure 4 F).…”

Section: Resultsmentioning

confidence: 99%

“…(A) In the fork recovery pathway, the ssDNA-RPA complex recruits some proteins. 72 , 77 Meanwhile, BRCA2 catalyzes the formation and stabilization of RAD51-ssDNA filaments, which protects nascent DNA from MRE11-mediated nucleolytic degradation. 69 , 78 Then, CHK1 is activated with the help of G2E3, 79 and the replication fork restarts after obstacle removal.…”

Section: Resultsmentioning

confidence: 99%