Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/5145596
- author
- 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
- organization
- publishing date
- 2015
- 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 Academy of Sciences
- external identifiers
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- pmid:25646469
- wos:000349446000077
- scopus:84923166583
- pmid:25646469
- 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
- 2016-04-01 10:54:34
- date last changed
- 2022-04-04 22:30:32
@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 Academy of 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 = {{https://lup.lub.lu.se/search/files/2225764/7762167}},
doi = {{10.1073/pnas.1418947112}},
volume = {{112}},
year = {{2015}},
}