title: 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.
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden;
authors: Andrea
authors: A
authors: Björkman
authors: Department of Biomedicine and Centre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark;
authors: Per
authors: P
authors: Qvist
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden;
authors: Likun
authors: L
authors: Du
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden;
authors: Margarita
authors: M
authors: Bartish
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden;
authors: Apostolos
authors: A
authors: Zaravinos
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden;
authors: Konstantinos
authors: K
authors: Georgiou
authors: Department of Biomedicine and Centre for Integrative Sequencing, Aarhus University, 8000 Aarhus, Denmark;
authors: Anders D
authors: AD
authors: Børglum
authors: Departments of Pathology and Laboratory Medicine and Human Genetics, University of California, Los Angeles, CA 90095; and.
authors: Richard A
authors: RA
authors: Gatti
authors: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund 22100, Sweden.
authors: Therese
authors: T
authors: Törngren
authors: Department of Laboratory Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden; qiang.pan-hammarstrom@ki.se.
authors: Qiang
authors: Q
authors: Pan-Hammarström
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D019313:BRCA1 Protein / Q000235:genetics*; D004260:DNA Repair; D006801:Humans; D017578:Immunoglobulin Class Switching; D011995:Recombination, Genetic
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human
keywords: B cells; BRCA1; alternative end-joining; immunoglobulin class switch recombination; nonhomologous end-joining
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