Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

Abstract

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1's function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.BRCA1 | nonhomologous end-joining | immunoglobulin class switch recombination | alternative end-joining | B cells

An immune-centric exploration of BRCA1 and BRCA2 germline mutation related breast and ovarian cancers

“…Looking from immune-centric point of view on patients with BRCA1/2 germline mutations, one wonders how BRCA1/2 deficiency influences the systemic immunity independent of its role in breast and ovarian tumorigenesis? Indeed, B-cell differentiation and maturation requires DDR [58] and BRCA1 protein have a direct role in B cells lymphomagenesis [59] suggesting the possible alterations in the systemic immunity of germline mutation carriers. In keeping with this, BRCA1/2 germline mutation carriers have higher risk of developing certain leukemias and lymphomas [60,61].…”

Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

“…The immunogenicity of HGSOC may involve other classes of tumour antigens, such as amplified or aberrant gene products arising from gene fusions. The B cell repertoire is altered in BRCA1 -mutant carriers 82 , suggesting another means by which this germline mutation might affect the tumour microenvironment of HGSOC. An improved understanding of the determinants of TIL density in HGSOC may assist in the development of immune checkpoint therapies in this disease.…”

PI3 Kinase and FOXO1 Transcription Factor Activity Differentially Control B Cells in the Germinal Center Light and Dark Zones

“…In contrast, DNA-repairassociated genes (like Fanconi gene family members Brca1 and Neil1) were downregulated. Some of these genes have previously been linked to GC programs like DNA editing and B cell expansion (Nguyen et al, 2014;Mori et al, 2009;Bjö rkman et al, 2015). Histologically, in the GCs of P110* and Foxo1 fl/fl animals, the network of activated follicular dendritic cells (FDCs), which precisely demarcates the LZ in control animals, extended through the entire GC structure and was populated by GC B cells with nuclear FOXO1 being barely detectable ( Figure 2F).…”