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

Björkman, Andrea; Qvist, Per; Du, Likun; Bartish, Margarita; Zaravinos, Apostolos; Georgiou, Konstantinos; Børglum, Anders D; Gatti, Richard A; Törngren, Therese LU and Pan-Hammarström, Qiang (2015) In Proceedings of the National Academy of Sciences 112(7). p.2157-2162
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Proceedings of the National Academy of Sciences
volume
112
issue
7
pages
2157 - 2162
publisher
National Acad Sciences
external identifiers
  • pmid:25646469
  • wos:000349446000077
  • scopus:84923166583
ISSN
1091-6490
DOI
10.1073/pnas.1418947112
language
English
LU publication?
yes
id
e82c0dda-a889-40d5-be13-83e2078bd61e (old id 5145596)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25646469?dopt=Abstract
date added to LUP
2015-03-03 20:21:56
date last changed
2017-07-02 03:20:42
@article{e82c0dda-a889-40d5-be13-83e2078bd61e,
  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.},
  author       = {Björkman, Andrea and Qvist, Per and Du, Likun and Bartish, Margarita and Zaravinos, Apostolos and Georgiou, Konstantinos and Børglum, Anders D and Gatti, Richard A and Törngren, Therese and Pan-Hammarström, Qiang},
  issn         = {1091-6490},
  language     = {eng},
  number       = {7},
  pages        = {2157--2162},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.},
  url          = {http://dx.doi.org/10.1073/pnas.1418947112},
  volume       = {112},
  year         = {2015},
}