The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

Libri, Alice; Marton, Timea; Deriano, Ludovic

doi:10.3389/fgene.2021.823943

Cited by 15 publications

(13 citation statements)

References 113 publications

(155 reference statements)

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“…Why is the SHLD complex, contrary to 53BP1, dispensable for RAG-induced DSB repair? Specific features of the V(D)J recombination reaction might provide clues to this question 2,51 . First, the RAG-cleavage and repair steps of the reaction are coupled, possibly limiting fortuitous end resection events.…”

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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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%

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

et al. 2022

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“…However, lymphopoiesis was even more severely suppressed, suggesting that DNA damage related to loss of RER is either more strictly controlled in lymphocytes, e.g. by induction of cell death, or that lymphocytes favor error-prone repair by NHEJ (Libri et al, 2022) and thereby massively accumulate fatal genome damage. Interestingly, RH2 hKO mice developed thrombocythemia, while production of all other blood cell lineages was impaired.…”

Section: Discussionmentioning

confidence: 99%

Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

Dressel

Natusch

Munz

et al. 2022

Preprint

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Cell-intrinsic response patterns control risks arising from genome-damaged cells, preventing malignant transformation. p53-dependent DNA damage responses halt the cell cycle and induce either repair, senescence or cell death. Cyclic-GMP-AMP synthase (cGAS) has emerged as a new principle detecting genome damage and activating complex response programs. This DNA sensor is activated by micronuclei, chromosome bridges and prolonged mitotic arrest. STING-responses downstream of cGAS can drive cells into senescence or cell death through the induction of antiproliferative type I interferons (IFN) and proapoptotic tumor necrosis factor. Herein, we investigated how DNA damage-dependent and DNA-damage independent chronic activation of cGAS/STING signaling impacts on hematopoiesis. Hematopoietic loss of ribonucleotide excision repair (RER) resulted in chromosomal instability and activation of the cGAS/STING/IFN axis. Mice with hematopoietic RER-deficiency displayed compromised hematopoietic stem cell (HSC) function resulting in cytopenia and ultimately developed leukemia. Additional loss of p53 largely rescued mature blood cell production at the cost of accelerated leukemogenesis, while concurrent loss of cGAS, STING or type I IFN signalling had no detectable effect on HSC function, cytopenia and leukemia development in RER-deficient hematopoiesis. Also in models of acute genome damage, cGAS was irrelevant for the initial cell loss as well as the subsequent recovery of hematopoiesis. In contrast, a constitutive STING gain-of-function mutation impaired HSC functions independently of DNA damage. Collectively, we present in vivo evidence that the cGAS/STING pathway does not influence the capacity of the hematopoietic system to cope with DNA damage. Nevertheless, chronic activation of STING dramatically reduced the fitness of HSCs.

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“…RAG-initiated DSBs are exclusively repaired by C-NHEJ, resulting from the synapsis of breaks held by the RAG post-cleavage complex (PCC) ( Figure 2D ) ( Teng and Schatz, 2015 ; Libri et al, 2021 ). RAG2 truncations or charge-neutralizing mutations switch the DSB repair pathway from C-NHEJ to alternative end-joining (A-EJ) and HR ( Corneo et al, 2007 ; Coussens et al, 2013 ; Gigi et al, 2014 ).…”

Section: V(d)j Recombinationmentioning

confidence: 99%

DNA Damage Response and Repair in Adaptive Immunity

Luo

Qiao²,

Zhang³

2022

Front. Cell Dev. Biol.

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The diversification of B-cell receptor (BCR), as well as its secreted product, antibody, is a hallmark of adaptive immunity, which has more specific roles in fighting against pathogens. The antibody diversification is from recombination-activating gene (RAG)-initiated V(D)J recombination, activation-induced cytidine deaminase (AID)-initiated class switch recombination (CSR), and V(D)J exon somatic hypermutation (SHM). The proper repair of RAG- and AID-initiated DNA lesions and double-strand breaks (DSBs) is required for promoting antibody diversification, suppressing genomic instability, and oncogenic translocations. DNA damage response (DDR) factors and DSB end-joining factors are recruited to the RAG- and AID-initiated DNA lesions and DSBs to coordinately resolve them for generating productive recombination products during antibody diversification. Recently, cohesin-mediated loop extrusion is proposed to be the underlying mechanism of V(D)J recombination and CSR, which plays essential roles in promoting the orientation-biased deletional end-joining . Here, we will discuss the mechanism of DNA damage repair in antibody diversification.

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The (Lack of) DNA Double-Strand Break Repair Pathway Choice During V(D)J Recombination

Cited by 15 publications

References 113 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

Clearance of genome-damaged cells from the hematopoietic system via p53 without contribution by the cGAS/STING axis

DNA Damage Response and Repair in Adaptive Immunity

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