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RAD51 family factors remodel the NHEJ system to modulate stress-induced biosynthesis of diterpenoid phytoalexins in rice.

ABSTRACT: Double-strand break (DSB) damage are primarily repaired via homologous recombination (HR) and non-homologous end joining (NHEJ) in Eukaryotes. We reveals that HR subcomplex RAD51A1-RAD51C in rice (Oryza sativa L.) inhibits classic NHEJ pathway while acts as a transcriptional mediator underlying alternative NHEJ signaling. RAD51C hijacks the KU70 at DSBs, facilitated by its partner RAD51A1 or TOP6B responding environmental cues (pathogens and 4℃). Consequently, the enhanced alternative NHEJ signaling generates the phosphorylated SOG1, which activates the regulatory network in diterpenoid phytoalexin biosynthesis and a group of enzyme genes in phenylpropanoid pathway. Intriguingly, SOG1-BRCA1-RAD51 associates with RAD51C-RAD51D-XRCC3 to form a transcription pre-initiation complex in this process. Phenotypically, chemical disease resistance and 4℃-conditioned stomatal closure are compromised in single mutants (atm-3, sog1, and rad51c-1), double mutants (rad51a1 rad51a2 and rad51d xrcc3). In summary, HR pathway integrates classic and alternative NHEJ pathways to orchestrate stress-activated specific metabolism in rice. Hierarchical collaboration of global DSB-repair machinerys enable plant adaptability to DSB-related environmental stresses.

ORGANISM(S): Oryza sativa

PROVIDER: GSE288025 | GEO | 2025/01/30

REPOSITORIES: GEO

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RAD51 family members remodel the NHEJ system to modulate stress-induced biosynthesis of diterpenoid phytoalexins in rice

Project description:Double-strand break (DSB) damage are primarily repaired via homologous recombination (HR) and non-homologous end joining (NHEJ) in Eukaryotes. We reveals that HR subcomplex RAD51A1-RAD51C in rice (Oryza sativa L.) inhibits classic NHEJ pathway while acts as a transcriptional mediator underlying alternative NHEJ signaling. RAD51C hijacks the KU70 at DSBs, facilitated by the interacting partner RAD51A1 or TOP6B responding environmental cues (pathogens and 4℃). Consequently, the enhanced alternative NHEJ signaling generates the phosphorylated SOG1, which activates the regulatory network in diterpenoid phytoalexin biosynthesis and a group of genes in phenylpropanoid pathway. Intriguingly, SOG1-BRCA1-RAD51 associates with RAD51C-RAD51D-XRCC3 forming a transcription pre-initiation complex in this process. Phenotypically, chemical disease resistance and 4℃-conditioned stomatal closure are compromised in single mutants (atm-3, sog1, and rad51c-1), double mutants (rad51a1 rad51a2 and rad51d xrcc3). In summary, HR pathway integrates classic and alternative NHEJ pathways to orchestrate stress-activated specific metabolism in rice plants. Hierarchical functional collaboration of global DSB-repair machinerys enable plant adaptability to DSB-related environmental stresses.

2025-01-27 | GSE287659 | GEO

DNA methylation is stable after MMEJ and NHEJ double strand break repair

Project description:DNA double strand breaks (DSBs) are a major source of mutations. Both non-homologous-end-joining (NHEJ) and microhomology-mediated-end-joining (MMEJ) DSB repair pathways are error prone and produce deletions, which can lead to cancer. DSBs also lead to epigenetic changes, including demethylation, which is involved in carcinogenesis. Of specific interest is the MMEJ repair pathway, as it requires methylation restoration around the break, as a result of the resection and formation of single stranded (ssDNA) intermediates. While, methylation patterns after homologous recombination (HR) have been partially studied, the methylation status after MMEJ and NHEJ remains poorly reported, and can be relevant for cancer. To study methylation patterns around DSB after NHEJ and MMEJ repair, we used targeted bisulfite-sequencing (BS-seq) to quantify methylation of dozens of single cell clones after induction of DSB by CRISPR. Each single cell clone was classified according to the sequence signature to a specific repair mechanism: NHEJ or MMEJ. Comparison of single cell clones after DSB to control cells, without DSB, demonstrated correct restoration of the methylation levels. No difference in methylation patterns was noticed when comparing NHEJ to MMEJ. Methylation levels in gene body, highly methylated CpGs (n=61, 4000 base pairs around DSB) and in low methylation CpGs (n=19), remained stable after both MMEJ and NHEJ. Gene body methylation persisted even on the background of DNMT3A R882C mutation, the most prevalent preleukemic mutation, in which the de novo methylation machinery is compromised. An exception observed in a single CpG site (ASXL1 995) which demonstrated elevated methylation rate after DSB repair only in the presence of WT DNMT3A. In summary, DNA methylation restoration demonstrated high fidelity after DSB both in methylated and unmethylated gene body, even in cases where DNA resections and deletions occurred.

2022-09-11 | E-MTAB-12037 | biostudies-arrayexpress

DNA Methylation is stable after MMEJ and NHEJ double strand break repair - OCI-AML3 dataset

2022-08-25 | E-MTAB-12061 | biostudies-arrayexpress

High-throughput capture of cis-rearrangement and trans-rearrangement sequence [LAM-HTGTS]

Project description:Cell cycle is a major determinant of DNA double-strand break (DSB) repair pathway choice with homologous recombination (HR) that is most active in S phase cells and non-homologous end-joining (NHEJ) that dominates in G1 phase cells. A third less well-defined mechanism, 'alternative end-joining', has been shown to promote error-prone repair in NHEJ- or HR-deficient cells. Here, we have used a physiologic system of NHEJ-mediated genomic rearrangements induced by the site-specific RAG1/2 endonuclease in G1 cells to investigate the fate of unrepaired G1 DSBs upon entry into the cell cycle. We show that, in the absence of XRCC4, alternative end-joining rescues RAG-induced DSB repair and promotes chromosome translocations upon G1 cell cycle exit.

2020-08-24 | GSE138136 | GEO

Igk locus capture-based target enrichment sequencing

2020-08-24 | GSE138135 | GEO

DROSHA is recruited to DNA damage sites by the MRN complex to promote non-homologous end-joining

Project description:The DNA damage response (DDR) is the signaling cascade that recognizes DNA double-strand breaks (DSB) and promotes their resolution via the DNA repair pathways of Non-Homologous End Joining (NHEJ) or Homologous Recombination (HR). We and others have shown that DDR activation requires DROSHA. However, whether DROSHA exerts its functions by associating with damage sites, what controls its recruitment and how DROSHA influences DNA repair, remains poorly understood. Here we show that DROSHA associates to DSBs independently from transcription. Neither H2AX, nor ATM nor DNA-PK kinase activities are required for its recruitment to break site. Rather, DROSHA interacts with RAD50 and inhibition of MRN by Mirin treatment abolishes this interaction. MRN inactivation by RAD50 knockdown or mirin treatment prevents DROSHA recruitment to DSB and, as a consequence, also 53BP1 recruitment. During DNA repair, DROSHA inactivation reduces NHEJ and boosts HR frequency. Indeed, DROSHA knockdown also increase the association of downstream HR factors such as RAD51 to DNA ends. Overall, our results demonstrate that DROSHA is recruited at DSBs by the MRN complex and direct DNA repair toward NHEJ.

2021-03-15 | GSE166631 | GEO

SCAI promotes DNA double-strand break repair in distinct chromosomal contexts

Project description:DNA double-strand breaks (DSBs) are highly cytotoxic DNA lesions, whose accurate repair by non-homologous end-joining (NHEJ) or homologous recombination (HR) is crucial for genome integrity and is strongly influenced by the local chromatin environment. Here, we identify SCAI (Suppressor of Cancer Cell Invasion) as a 53BP1-interacting chromatin-associated protein that promotes the functionality of several DSB repair pathways in mammalian cells. SCAI undergoes prominent enrichment at DSB sites through dual mechanisms involving 53BP1-dependent recruitment to DSB-surrounding chromatin and 53BP1-independent accumulation at resected DSBs. Cells lacking SCAI display reduced DSB repair capacity, hypersensitivity to DSB-inflicting agents and genome instability. We demonstrate that SCAI is a mediator of 53BP1-dependent repair of heterochromatin-associated DSBs, facilitating ATM kinase signaling at DSBs in repressive chromatin environments. Moreover, we establish an important role of SCAI in meiotic recombination, as SCAI deficiency in mice leads to germ cell loss and subfertility associated with impaired retention of the DMC1 recombinase on meiotic chromosomes. Collectively, our findings uncover SCAI as a physiologically important component of both NHEJ- and HR-mediated pathways that potentiates DSB repair efficiency in specific chromatin contexts.

2016-12-12 | PXD004912 | Pride

Transcriptome changes of Hela cells with blocking classical and alternative non-homologous end-joining (NHEJ) pathways

Project description:Purpose: The recombinant endonucleases introduce double-strand breaks (DSBs) in genomic DNA at targeted sites and non-homologous end-joining (NHEJ) pathways repair the breaks introducing indels into the genome. To investigate whether there is another NHEJ pathway or if A-NHEJ and C-NHEJ are redundant, we examined NHEJ edits in HeLa cells. Methods: To test among these possibilities, we engineered a NHEJ reporter system using targeted TALEN induced double strand DNA breaks. C-NHEJ was blocked in XRCC4(-/-) cells and A-NHEJ was blocked pharmacologically with mirin. To assess how NHEJ was maintained, differentially expressed genes were determined by RNA-Seq. Results: When both C-NHEJ and A-NHEJ are blocked, edits were still observed. No changes in expression of DNA repair genes was observed. However, when both NHEJ pathways were blocked, genes from several pathways including DNA damage response, hypoxic response, chromatin packaging, p53 response and two genes that stimulate homologous recombination were differentially expressed. Conclusions: NHEJ is maintained when both NHEJ pathways are blocked through a transcriptional response that must compensate for the inhibited steps in both pathways.

2020-12-31 | GSE135274 | GEO

RNA-seq analysis of PRMT5-regulated genes in irradiated/non-irradiated LNCaP cells

Project description:DNA Double-strand break (DSB) repair is critical for cell survival and genome integrity. Upon recognition of DSBs, repair proteins are transiently upregulated to facilitate repair through homologous recombination (HR) or non-homologous end joining (NHEJ). We present evidence that PRMT5 cooperates with pICln to function as a master epigenetic activator of DNA damage response (DDR) genes involved in HR, NHEJ, and G2 arrest (including RAD51, BRCA1, and BRCA2) to upregulate gene expression upon DNA damage. Contrary to the predominant role of PRMT5 as an epigenetic repressor, our results demonstrate that PRMT5 and pICln can activate gene expression, potentially independent of PRMT5’s obligate cofactor MEP50. Targeting PRMT5 or pICln hinders repair of DSBs in multiple cancer cell lines, and both PRMT5 and pICln expression positively correlates with DDR genes across 32 clinical cancer data sets. Thus, targeting PRMT5 or pICln may be explored in combination with radiation or chemotherapy for cancer treatment.

2019-12-05 | GSE111620 | GEO

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Project description:53BP1 regulates DNA end-joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting RIF1 and shieldin, a poorly understood DNA-binding complex. The 53BP1-RIF1-shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate non-homologous end-joining (NHEJ). However, how this axis regulates DNA end-joining and HR suppression remains unresolved. We investigated shieldin and its interplay with CST, a complex recently implicated in 53BP1-dependent activities. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination co-reliant on both complexes. DNA damage-responsive signalling promotes shieldin-CST interaction, demonstrating shieldin as a DSB-specific CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin-CST. Lastly, 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient cells independently of shieldin. These findings showcase the resilience of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.

2024-08-27 | PXD045534 | Pride

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