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

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DOI

    Andrea Björkman, Karolinska Instituttet, Sweden
  • Per Qvist
  • Likun Du, Karolinska Instituttet, SwedenMargarita Bartish, Karolinska Instituttet, SwedenApostolos Zaravinos, Karolinska Instituttet, SwedenKonstatinos Georgiou, Karolinska Instituttet, Sweden
  • Anders Børglum
  • Richard A Gatti, UCLA, United StatesTherese Törngren, University of Lund, Lund, SwedenQiang Pan-Hammerström, Karolinska Instituttet, Sweden
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.
Original languageEnglish
JournalPNAS (Proceedings of the National Academy of Sciences of the United States of America)
Volume112
Issue number7
Pages (from-to)2157-2162
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 7 Jan 2015

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