MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair

Krijger, Inge de; Föhr, Bastian; Pérez, Santiago Hernández; Vincendeau, Estelle; Serrat, Judit; Thouin, Alexander Marc; Susvirkar, Vivek; Lescale, Chloé; Paniagua, Inés; Hoekman, Liesbeth; Kaur, Simranjeet; Altelaar, Maarten; Deriano, Ludovic; Faesen, Alex C.; Jacobs, Jacqueline J.L.

doi:10.1038/s41467-021-25724-y

Cited by 21 publications

(33 citation statements)

References 61 publications

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“…This model is consistent with previous work suggesting that 53BP1 acts primarily to ensure the fidelity of DSB repair 24 , 67 . In this view, the dynamic nature of SHLD complex assembly and disassembly would be an important parameter to allow for multiple DSB repair machineries to accurately process and join DSB ends 56 , 68 , 69 . The nature of the alt-NHEJ pathway acting during CSR remains to be fully established 10 , 11 , 23 .…”

Section: Discussionmentioning

confidence: 99%

“…It was recently reported that DSB end protection might in fact play a limited role in the ability of 53BP1 to support CSR, based on the observation that a mutant form of 53BP1 defective for RIF1 recruitment still supports robust CSR 55 . Yet, B cells deficient for any component of the SHLD complex as well as for RIF1 display defective CSR [27][28][29][30][31][32][33][34][56][57][58] . The recent identification of distinct modes of RIF1 and SHLD recruitment at DSBs and action to promote DNA repair might partially explain this discrepancy 59 .…”

Section: Discussionmentioning

confidence: 99%

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SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

et al. 2022

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SHLD1 is part of the Shieldin (SHLD) complex, which acts downstream of 53BP1 to counteract DNA double-strand break (DSB) end resection and promote DNA repair via non-homologous end-joining (NHEJ). While 53BP1 is essential for immunoglobulin heavy chain class switch recombination (CSR), long-range V(D)J recombination and repair of RAG-induced DSBs in XLF-deficient cells, the function of SHLD during these processes remains elusive. Here we report that SHLD1 is dispensable for lymphocyte development and RAG-mediated V(D)J recombination, even in the absence of XLF. By contrast, SHLD1 is essential for restricting resection at AID-induced DSB ends in both NHEJ-proficient and NHEJ-deficient B cells, providing an end-protection mechanism that permits productive CSR by NHEJ and alternative end-joining. Finally, we show that this SHLD1 function is required for orientation-specific joining of AID-initiated DSBs. Our data thus suggest that 53BP1 promotes V(D)J recombination and CSR through two distinct mechanisms: SHLD-independent synapsis of V(D)J segments and switch regions within chromatin, and SHLD-dependent protection of AID-DSB ends against resection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

et al. 2022

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“…This slow, but spontaneous, conversion is a rate-limiting step in the assembly of the respective effector complex. Indeed, we previously showed that REV7-SHLD3 complex formation takes several hours (de Krijger et al, 2021). However, as described in Figure 3b, the purified REV7 is already in the ‘closed’ state, so potentially no conversion would be necessary.…”

Section: Resultsmentioning

confidence: 99%

“…Central to the unusual interaction mechanism of REV7 is the extraordinary ability to wrap its C-terminal tail (‘seat-belt’) around an interacting peptide motif of a client protein, thereby creating a very stable complex. Both Polζ and Shieldin incorporate a dimer of REV7 molecules, which are essential for their function in vitro and in cells (de Krijger et al, 2021; Malik et al, 2020; Rizzo et al, 2018). Using the seat-belt mechanism, REV7 captures the REV7-binding-motifs (RBM) in SHLD3 (residues 49 to 62) and REV3 (RBM1, residues 1875 to 1896, and RBM2, residues 1991 to 2012) (Dai et al, 2020; Hara et al, 2010; Rizzo et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Molecular insights into human Shieldin complex assembly and recruitment to DSBs

Susvirkar

Faesen

2022

Preprint

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The Shieldin complex represses end resection at DNA double-strand breaks (DSBs) and thereby serves as a pro-non homologous end joining (NHEJ) factor in the G1 phase of the cell cycle. Its components SHLD1, SHLD2, SHLD3 and REV7 are recruited in a hierarchical fashion. SHLD3 and REV7 localize first to DSBs, while the subsequently recruited SHLD2 is the only known DNA binding protein in the complex. The molecular details of the initial recruitment of SHLD3 and REV7, and the subsequent assembly of Shieldin on DSBs are unclear. Here, we report the identification of a promiscuous DNA binding domain in the C-terminal half of SHLD3. At the N-terminus, SHLD3 interacts with a dimer of REV7 molecules. We show that the interaction between SHLD3 and the first REV7 is remarkably slow, which is likely due to the substantial activation energy required to remodel mobile structural elements within the REV7 molecule to allow for binding to SHLD3. In contrast, the interaction between SHLD3 and SHLD2 with a second REV7 molecule is fast and does not require structural remodelling. Overall, these results provide insights into the rate-limiting step of the molecular assembly and recruitment of Shieldin complex at DNA DSBs.

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“…Upregulation of MAD2L2 (also known as MAD2B or REV7 ) decreases DNA end resection, which increases NHEJ and chromosomal abnormalities, resulting mitotic catastrophe in PARP inhibitor treated HR-proficient cells. In addition, MAD2L2 can also inhibit end-resection in irradiation (IR)-induced DNA double-strand breaks (DSBs) ( Boersma et al, 2015 ; Simonetta et al, 2018 ; De Krijger et al, 2021 ). MAD2L2 accelerates end-joining of DNA double-strand breaks in several settings, including immunoglobulin class switch recombination through ATM kinase activity ( Xu et al, 2015 ; Batenburg et al, 2017 ; Noordermeer et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer

et al. 2022

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Objective: The purpose of this study was to investigate the associations of genetic variants in double-strand break (DSB) repair pathway genes with prognosis in patients with lung cancer treated with platinum-based chemotherapy.Methods: Three hundred ninety-nine patients with lung cancer who received platinum-based chemotherapy for at least two cycles were included in this study. A total of 35 single nucleotide polymorphisms (SNPs) in DSB repair, base excision repair (BER), and nucleotide excision repair (NER) repair pathway genes were genotyped, and were used to evaluate the overall survival (OS) and the progression-free survival (PFS) of patients who received platinum-based chemotherapy using Cox proportional hazard models.Results: The PFS of patients who carried the MAD2L2 rs746218 GG genotype was shorter than that in patients with the AG or AA genotypes (recessive model: p = 0.039, OR = 5.31, 95% CI = 1.09–25.93). Patients with the TT or GT genotypes of TNFRSF1A rs4149570 had shorter OS times than those with the GG genotype (dominant model: p = 0.030, OR = 0.57, 95% CI = 0.34–0.95). We also investigated the influence of age, gender, histology, smoking, stage, and metastasis in association between SNPs and OS or PFS in patients with lung cancer. DNA repair gene SNPs were significantly associated with PFS and OS in the subgroup analyses.Conclusion: Our study showed that variants in MAD2L2 rs746218 and TNFRSF1A rs4149570 were associated with shorter PFS or OS in patients with lung cancer who received platinum-based chemotherapy. These variants may be novel biomarkers for the prediction of prognosis of patients with lung cancer who receive platinum-based chemotherapy.

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MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair

Cited by 21 publications

References 61 publications

SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination

Molecular insights into human Shieldin complex assembly and recruitment to DSBs

Genetic Variants in Double-Strand Break Repair Pathway Genes to Predict Platinum-Based Chemotherapy Prognosis in Patients With Lung Cancer

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