V(D)J Recombination: Recent Insights in Formation of the Recombinase Complex and Recruitment of DNA Repair Machinery

Christie, Shaun M.; Fijen, Carel; Rothenberg, Eli

doi:10.3389/fcell.2022.886718

Cited by 20 publications

(42 citation statements)

References 142 publications

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“…This event is orchestrated by recombinase-activating genes (RAG), which recognizes recombination signal sequences to mediate interstitial deletions at these genomic loci. Following, the terminal deoxynucleotidyl transferase (TdT) displays template-independent activity and adds nucleotides to the junctions 41 . Here, we demonstrate that most IKZF1 deletions are associated with genetic signatures of RAG and TdT activity, thus explaining the reason for its recurrence in B-ALL.…”

Section: Discussionmentioning

confidence: 99%

The recombinome of IKZF1 deletions in B-ALL

Lopes

Meyer

Bouzada

et al. 2023

Preprint

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IKZF1 deletions are associated with an increased risk of relapse in B-cell precursor acute lymphoblastic leukemia (B-ALL), and their accurate detection has great clinical impact. Here, we included four international cohorts of pediatric and adult patients with B-ALL, and reviewed literature to illustrate the recombination map of IKZF1 deletions, with a focus at non-recurrent deletions. We provide a substantial basis for the improvement of diagnostic methods based on MLPA and multiplex PCR for the identification of IKZF1 deletions, and also demonstrate that rare IKZF1 deletions increase the incidence of relapse in these patients. Of note, non-recurrent deletions comprised a wide range of alterations, but the majority were Δ1 and Δ1–3. They were often associated with reciprocal IKZF1 fusions. So far, a total of 23 IKZF1 gene fusions were identified in B-ALL. We also verified the occurrence of the heptamer sequence (E-value: 9.9 x 10− 9) and an enrichment of GC nucleotides (71% versus 56%; P value = 4.9 x 10− 3) exclusively within breakpoint clusters, suggesting that RAG recombination and TdT activity may promote the majority of IKZF1 deletions, although rare types of alterations may be associated with other molecular mechanism of leukemogenesis, such as microhomology-mediated end joining.

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Section: Discussionmentioning

confidence: 99%

The recombinome of IKZF1 deletions in B-ALL

Lopes

Meyer

Bouzada

et al. 2023

Preprint

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“…RAG1/RAG2 also affects NK cell differentiation and plays a role in DNA transposition 41,42 . Double-stranded breaks induced by the RAG complex are repaired by ATM, a serine/threonine kinase that orchestrates DNA repair at double-strand breaks 40,[43][44][45] .…”

Section: Introductionmentioning

confidence: 99%

“…In our original paper, two of the ultrarare variants we found are in genes that affect DDR ( PPM1D and CHK2 ), and one induces DNA breaks ( RAG1 ). RAG1 , along with RAG2 , codes for endonucleases that induce DNA double-strand breaks responsible for the somatic recombination that generates immune cell diversity in B- and T-lymphocytes 1, 38, 39 . RAG1/RAG2 also affects NK cell differentiation and plays a role in DNA transposition 40, 41 .…”

Section: Introductionmentioning

confidence: 99%

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

Cunningham,

Frankovich,

Dubin

et al. 2024

Preprint

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Acute onset of severe psychiatric symptoms or regression may occur in children with premorbid neurodevelopmental disorders, although typically developing children can also be affected. Infections or other stressors are likely triggers. The underlying causes are unclear, but a current hypothesis suggests the convergence of genes that influence neuronal and immunological function. We previously identified 11 genes in Pediatric Acute-Onset Neuropsychiatry Syndrome (PANS), in which two classes of genes related to either synaptic function or the immune system were found. Among the latter, three affect the DNA damage response (DDR):PPM1D, CHK2,andRAG1. We now report an additional 17 cases with mutations inPPM1Dand other DDR genes in patients with acute onset of psychiatric symptoms and/or regression that were classified by their clinicians as PANS or another inflammatory brain condition. The genes include clusters affecting p53 DNA repair (PPM1D,ATM, ATR,53BP1,andRMRP), and the Fanconi Anemia Complex (FANCE, SLX4/FANCP, FANCA, FANCI,andFANCC). We hypothesize that defects in DNA repair genes, in the context of infection or other stressors, could lead to an increase in cytosolic DNA in immune cells triggering DNA sensors, such as cGAS-STING and AIM2 inflammasomes. These findings could lead to new treatment strategies.

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“…RAG1 and RAG2 generate DNA double‐stranded breaks (DSBs) between the V, D, and J segments and RSS (Schatz & Swanson, 2011). Then, these segments are joined by the classical non‐homologous end‐joining (c‐NHEJ) pathway to complete V(D)J recombination (Christie et al, 2022). Furthermore, HMGB1 also plays a critical role during V(D)J recombination by enhancing the assembly of RAG1/2‐recombination signal sequence (RSS) DNA complexes (Dai et al, 2005), and so it is required for efficient RAG1/2‐mediated recombination (Thwaites et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

HIV‐1 integrase inhibitor raltegravir promotes DNA damage‐induced apoptosis in multiple myeloma

et al. 2023

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Raltegravir, the first integrase inhibitor approved for the treatment of HIV infection, has been implicated as a promising potential in cancer treatment. Therefore, the present study aimed to investigate the repurposing of raltegravir as an anticancer agent and its mechanism of action in multiple myeloma (MM). Human MM cell lines (RPMI‐8226, NCI H929, and U266) and normal peripheral blood mononuclear cells (PBMCs) were cultured with different concentrations of raltegravir for 48 and 72 h. Cell viability and apoptosis were then measured by MTT and Annexin V/PI assays, respectively. Protein levels of cleaved PARP, Bcl‐2, Beclin‐1, and phosphorylation of histone H2AX were detected by Western blotting. In addition, the mRNA levels of V(D)J recombination and DNA repair genes were analyzed using qPCR. Raltegravir treatment for 72 h significantly decreased cell viability, increased apoptosis, and DNA damage in MM cells while having minimum toxicity on cell viability of normal PBMCs approximately from 200 nM (0.2 μM; p < .01 for U66 and p < .0001 for NCI H929 and RPMI 8226 cells). Furthermore, raltegravir treatment altered the mRNA levels of V(D)J recombination and DNA repair genes. We report for the first time that treatment with raltegravir is associated with decreased cell viability, apoptosis induction, DNA damage accumulation, and alteration of mRNA expression of genes involved in V(D)J recombination and DNA repair in MM cell lines, all of which show its potential for anti‐myeloma effects. Hence, raltegravir may significantly impact the treatment of MM, and further studies are required to confirm its efficacy and mechanism of action in more detail in patient‐derived myeloma cells and in‐vivo models.

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V(D)J Recombination: Recent Insights in Formation of the Recombinase Complex and Recruitment of DNA Repair Machinery

Cited by 20 publications

References 142 publications

The recombinome of IKZF1 deletions in B-ALL

The recombinome of IKZF1 deletions in B-ALL

Ultrarare Variants in DNA Damage Repair Genes in Pediatric Acute-Onset Neuropsychiatric Syndrome or Acute Behavioral Regression in Neurodevelopmental Disorders

HIV‐1 integrase inhibitor raltegravir promotes DNA damage‐induced apoptosis in multiple myeloma

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