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Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4

The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined b...

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Autores principales: Boboila, Cristian, Yan, Catherine, Wesemann, Duane R., Jankovic, Mila, Wang, Jing H., Manis, John, Nussenzweig, Andre, Nussenzweig, Michel, Alt, Frederick W.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822597/
https://www.ncbi.nlm.nih.gov/pubmed/20142431
http://dx.doi.org/10.1084/jem.20092449
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author Boboila, Cristian
Yan, Catherine
Wesemann, Duane R.
Jankovic, Mila
Wang, Jing H.
Manis, John
Nussenzweig, Andre
Nussenzweig, Michel
Alt, Frederick W.
author_facet Boboila, Cristian
Yan, Catherine
Wesemann, Duane R.
Jankovic, Mila
Wang, Jing H.
Manis, John
Nussenzweig, Andre
Nussenzweig, Michel
Alt, Frederick W.
author_sort Boboila, Cristian
collection PubMed
description The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; “MH-mediated” joins) or no homologies (“direct” joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via “alternative” end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and Lig4. Ku70- or Ku80-deficient B cells have reduced, but still substantial, CSR. Strikingly, B cells deficient for both Ku plus Lig4 undergo CSR similarly to Ku-deficient B cells, firmly demonstrating that an A-EJ pathway distinct from C-NHEJ can catalyze CSR end-joining. Ku-deficient or Ku- plus Lig4-deficient B cells are also biased toward MH-mediated CSR joins; but, in contrast to XRCC4- or Lig4-deficient B cells, generate substantial numbers of direct CSR joins. Our findings suggest that more than one form of A-EJ can function in CSR.
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spelling pubmed-28225972010-08-15 Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4 Boboila, Cristian Yan, Catherine Wesemann, Duane R. Jankovic, Mila Wang, Jing H. Manis, John Nussenzweig, Andre Nussenzweig, Michel Alt, Frederick W. J Exp Med Article The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; “MH-mediated” joins) or no homologies (“direct” joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via “alternative” end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and Lig4. Ku70- or Ku80-deficient B cells have reduced, but still substantial, CSR. Strikingly, B cells deficient for both Ku plus Lig4 undergo CSR similarly to Ku-deficient B cells, firmly demonstrating that an A-EJ pathway distinct from C-NHEJ can catalyze CSR end-joining. Ku-deficient or Ku- plus Lig4-deficient B cells are also biased toward MH-mediated CSR joins; but, in contrast to XRCC4- or Lig4-deficient B cells, generate substantial numbers of direct CSR joins. Our findings suggest that more than one form of A-EJ can function in CSR. The Rockefeller University Press 2010-02-15 /pmc/articles/PMC2822597/ /pubmed/20142431 http://dx.doi.org/10.1084/jem.20092449 Text en © 2010 Boboila et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Boboila, Cristian
Yan, Catherine
Wesemann, Duane R.
Jankovic, Mila
Wang, Jing H.
Manis, John
Nussenzweig, Andre
Nussenzweig, Michel
Alt, Frederick W.
Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title_full Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title_fullStr Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title_full_unstemmed Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title_short Alternative end-joining catalyzes class switch recombination in the absence of both Ku70 and DNA ligase 4
title_sort alternative end-joining catalyzes class switch recombination in the absence of both ku70 and dna ligase 4
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2822597/
https://www.ncbi.nlm.nih.gov/pubmed/20142431
http://dx.doi.org/10.1084/jem.20092449
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