BRCT-domain protein BRIT1 influences class switch recombination Journal Article

Authors: Yen, W. F.; Chaudhry, A.; Vaidyanathan, B.; Yewdell, W. T.; Pucella, J. N.; Sharma, R.; Liang, Y.; Li, K.; Rudensky, A. Y.; Chaudhuri, J.
Article Title: BRCT-domain protein BRIT1 influences class switch recombination
Abstract: DNA double-strand breaks (DSBs) serve as obligatory intermediates for Ig heavy chain (Igh) class switch recombination (CSR). The mechanisms by which DSBs are resolved to promote long-range DNA end-joining while suppressing genomic instability inherently associated with DSBs are yet to be fully elucidated. Here, we use a targeted short-hairpin RNA screen in a B-cell lymphoma line to identify the BRCT-domain protein BRIT1 as an effector of CSR. We show that conditional genetic deletion of BRIT1 in mice leads to a marked increase in unrepaired Igh breaks and a significant reduction in CSR in ex vivo activated splenic B cells. We find that the C-terminal tandem BRCT domains of BRIT1 facilitate its interaction with phosphorylated H2AX and that BRIT1 is recruited to the Igh locus in an activation-induced cytidine deaminase (AID) and H2AX-dependent fashion. Finally, we demonstrate that depletion of another BRCT-domain protein, MDC1, in BRIT1-deleted B cells increases the severity of CSR defect over what is observed upon loss of either protein alone. Our results identify BRIT1 as a factor in CSR and demonstrate that multiple BRCT-domain proteins contribute to optimal resolution of AID-induced DSBs. © 2017, National Academy of Sciences. All rights reserved.
Keywords: dna repair; class switch recombination; b cells; mdc1; brct domains
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 31
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2017-08-01
Start Page: 8354
End Page: 8359
Language: English
DOI: 10.1073/pnas.1708211114
PROVIDER: scopus
PMCID: PMC5547652
PUBMED: 28724724
Notes: Article -- Export Date: 5 September 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Alexander Rudensky
    143 Rudensky
  2. Wei-Feng Yen
    12 Yen
  3. William Theodore Yewdell
    16 Yewdell
  4. Rahul Sharma
    5 Sharma