Chloé Lescale, Timea Marton, Amaury Vaysse, Guillaume Rode, Estelle Vincendeau, Alice Libri, François Dossin, Ludovic Deriano
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引用次数: 0
Abstract
Downstream of 53BP1-RIF1 lies the Shieldin (SHLD) protein complex, which comprises MAD2L2/REV7, SHLD3, SHLD2, and SHLD1, and the CTC1-STN1-TEN1 (CST) complex. During immunoglobulin heavy-chain (Igh) class switch recombination (CSR), 53BP1-RIF1-SHLD promotes productive end-joining by limiting resection of activation-induced cytidine deaminase (AID)-generated DNA double-strand break (DSB) ends. The precise role of the CST complex and its interplay with SHLD during CSR is however elusive. Here, we established AID-inducible B cell lines deficient for CTC1, SHLD1, or both and analyzed CSR in these cells. We show that stimulated CTC1-deficient B cells are defective for IgM-to-IgA class switching, accumulate Igh chromosome breaks and translocations, and display increased end-resection and micro-homology usage at switching sites, demonstrating that CTC1 is essential to suppress alternative end-joining during CSR. We show that CTC1 and SHLD1 are epistatic in preventing exacerbated DNA end resection and genetic instability during CSR. Moreover, using a complementation approach in Shld1 knockout splenic B cells, we show that a SHLD1 mutant defective in CST binding (SHLD1ΔLDLP) is fully proficient for IgM-to-IgG1, IgG2b, IgG3, and IgA class switching, thus demonstrating that the SHLD1-CTC1 interaction through this motif is dispensable for CST and SHLD functions in promoting CSR.
期刊介绍:
The European Journal of Immunology (EJI) is an official journal of EFIS. Established in 1971, EJI continues to serve the needs of the global immunology community covering basic, translational and clinical research, ranging from adaptive and innate immunity through to vaccines and immunotherapy, cancer, autoimmunity, allergy and more. Mechanistic insights and thought-provoking immunological findings are of interest, as are studies using the latest omics technologies. We offer fast track review for competitive situations, including recently scooped papers, format free submission, transparent and fair peer review and more as detailed in our policies.