SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus
Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic l...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ling, Alexanda K [verfasserIn] Munro, Meagan [verfasserIn] Chaudhary, Natasha [verfasserIn] Li, Conglei [verfasserIn] Berru, Maribel [verfasserIn] Wu, Brendan [verfasserIn] Durocher, Daniel [verfasserIn] Martin, Alberto [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: EMBO Reports - Nature Publishing Group UK, 2023, 21(2020), 8 vom: 17. Juni |
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| Übergeordnetes Werk: |
volume:21 ; year:2020 ; number:8 ; day:17 ; month:06 |
| Links: |
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| DOI / URN: |
10.15252/embr.201949823 |
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| Katalog-ID: |
SPR058138188 |
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| 100 | 1 | |a Ling, Alexanda K |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
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| 520 | |a Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. | ||
| 520 | |a Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. | ||
| 520 | |a Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. | ||
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| 650 | 4 | |a class switch recombination |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a shieldin |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a mouse |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Munro, Meagan |e verfasserin |4 aut | |
| 700 | 1 | |a Chaudhary, Natasha |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Conglei |e verfasserin |4 aut | |
| 700 | 1 | |a Berru, Maribel |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Brendan |e verfasserin |0 (orcid)0000-0002-2892-864X |4 aut | |
| 700 | 1 | |a Durocher, Daniel |e verfasserin |0 (orcid)0000-0003-3863-8635 |4 aut | |
| 700 | 1 | |a Martin, Alberto |e verfasserin |0 (orcid)0000-0002-0795-0418 |4 aut | |
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10.15252/embr.201949823 doi (DE-627)SPR058138188 (SPR)embr.201949823-e DE-627 ger DE-627 rakwb eng Ling, Alexanda K verfasserin aut SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 Munro, Meagan verfasserin aut Chaudhary, Natasha verfasserin aut Li, Conglei verfasserin aut Berru, Maribel verfasserin aut Wu, Brendan verfasserin (orcid)0000-0002-2892-864X aut Durocher, Daniel verfasserin (orcid)0000-0003-3863-8635 aut Martin, Alberto verfasserin (orcid)0000-0002-0795-0418 aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 21(2020), 8 vom: 17. Juni (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:21 year:2020 number:8 day:17 month:06 https://dx.doi.org/10.15252/embr.201949823 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 21 2020 8 17 06 |
| spelling |
10.15252/embr.201949823 doi (DE-627)SPR058138188 (SPR)embr.201949823-e DE-627 ger DE-627 rakwb eng Ling, Alexanda K verfasserin aut SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 Munro, Meagan verfasserin aut Chaudhary, Natasha verfasserin aut Li, Conglei verfasserin aut Berru, Maribel verfasserin aut Wu, Brendan verfasserin (orcid)0000-0002-2892-864X aut Durocher, Daniel verfasserin (orcid)0000-0003-3863-8635 aut Martin, Alberto verfasserin (orcid)0000-0002-0795-0418 aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 21(2020), 8 vom: 17. Juni (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:21 year:2020 number:8 day:17 month:06 https://dx.doi.org/10.15252/embr.201949823 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 21 2020 8 17 06 |
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10.15252/embr.201949823 doi (DE-627)SPR058138188 (SPR)embr.201949823-e DE-627 ger DE-627 rakwb eng Ling, Alexanda K verfasserin aut SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 Munro, Meagan verfasserin aut Chaudhary, Natasha verfasserin aut Li, Conglei verfasserin aut Berru, Maribel verfasserin aut Wu, Brendan verfasserin (orcid)0000-0002-2892-864X aut Durocher, Daniel verfasserin (orcid)0000-0003-3863-8635 aut Martin, Alberto verfasserin (orcid)0000-0002-0795-0418 aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 21(2020), 8 vom: 17. Juni (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:21 year:2020 number:8 day:17 month:06 https://dx.doi.org/10.15252/embr.201949823 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 21 2020 8 17 06 |
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10.15252/embr.201949823 doi (DE-627)SPR058138188 (SPR)embr.201949823-e DE-627 ger DE-627 rakwb eng Ling, Alexanda K verfasserin aut SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 Munro, Meagan verfasserin aut Chaudhary, Natasha verfasserin aut Li, Conglei verfasserin aut Berru, Maribel verfasserin aut Wu, Brendan verfasserin (orcid)0000-0002-2892-864X aut Durocher, Daniel verfasserin (orcid)0000-0003-3863-8635 aut Martin, Alberto verfasserin (orcid)0000-0002-0795-0418 aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 21(2020), 8 vom: 17. Juni (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:21 year:2020 number:8 day:17 month:06 https://dx.doi.org/10.15252/embr.201949823 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 21 2020 8 17 06 |
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10.15252/embr.201949823 doi (DE-627)SPR058138188 (SPR)embr.201949823-e DE-627 ger DE-627 rakwb eng Ling, Alexanda K verfasserin aut SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 Munro, Meagan verfasserin aut Chaudhary, Natasha verfasserin aut Li, Conglei verfasserin aut Berru, Maribel verfasserin aut Wu, Brendan verfasserin (orcid)0000-0002-2892-864X aut Durocher, Daniel verfasserin (orcid)0000-0003-3863-8635 aut Martin, Alberto verfasserin (orcid)0000-0002-0795-0418 aut Enthalten in EMBO Reports Nature Publishing Group UK, 2023 21(2020), 8 vom: 17. Juni (DE-627)320645622 (DE-600)2025376-X 1469-3178 nnns volume:21 year:2020 number:8 day:17 month:06 https://dx.doi.org/10.15252/embr.201949823 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4315 GBV_ILN_4317 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 21 2020 8 17 06 |
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Enthalten in EMBO Reports 21(2020), 8 vom: 17. Juni volume:21 year:2020 number:8 day:17 month:06 |
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Enthalten in EMBO Reports 21(2020), 8 vom: 17. Juni volume:21 year:2020 number:8 day:17 month:06 |
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B cell BRCA1 class switch recombination shieldin mouse |
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Ling, Alexanda K @@aut@@ Munro, Meagan @@aut@@ Chaudhary, Natasha @@aut@@ Li, Conglei @@aut@@ Berru, Maribel @@aut@@ Wu, Brendan @@aut@@ Durocher, Daniel @@aut@@ Martin, Alberto @@aut@@ |
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Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract The recently described Shieldin complex inhibits DNA resection. 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Ling, Alexanda K |
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Ling, Alexanda K misc B cell misc BRCA1 misc class switch recombination misc shieldin misc mouse SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
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SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus B cell (dpeaa)DE-He213 BRCA1 (dpeaa)DE-He213 class switch recombination (dpeaa)DE-He213 shieldin (dpeaa)DE-He213 mouse (dpeaa)DE-He213 |
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misc B cell misc BRCA1 misc class switch recombination misc shieldin misc mouse |
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SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
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SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
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Ling, Alexanda K Munro, Meagan Chaudhary, Natasha Li, Conglei Berru, Maribel Wu, Brendan Durocher, Daniel Martin, Alberto |
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Elektronische Aufsätze |
| author-letter |
Ling, Alexanda K |
| doi_str_mv |
10.15252/embr.201949823 |
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(ORCID)0000-0002-2892-864X (ORCID)0000-0003-3863-8635 (ORCID)0000-0002-0795-0418 |
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(orcid)0000-0002-2892-864X (orcid)0000-0003-3863-8635 (orcid)0000-0002-0795-0418 |
| author2-role |
verfasserin |
| title_sort |
shld2 promotes class switch recombination by preventing inactivating deletions within the igh locus |
| title_auth |
SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
| abstract |
Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. © The Author(s) 2020 |
| abstractGer |
Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. © The Author(s) 2020 |
| abstract_unstemmed |
Abstract The newly identified shieldin complex, composed of SHLD1, SHLD2, SHLD3, and REV7, lies downstream of 53BP1 and acts to inhibit DNA resection and promote NHEJ. Here, we show that Shld2−/− mice have defective class switch recombination (CSR) and that loss of SHLD2 can suppress the embryonic lethality of a Brca1Δ11 mutation, highlighting its role as a key effector of 53BP1. Lymphocyte development and RAG1/2‐mediated recombination were unaffected by SHLD2 deficiency. Interestingly, a significant fraction of Shld2−/− primary B‐cells and 53BP1‐ and shieldin‐deficient CH12F3‐2 B‐cells permanently lose expression of immunoglobulin upon induction of CSR; this population of Ig‐negative cells is also seen in other NHEJ‐deficient cells and to a much lesser extent in WT cells. This loss of Ig is due to recombination coupled with overactive resection and loss of coding exons in the downstream acceptor constant region. Collectively, these data show that SHLD2 is the key effector of 53BP1 and critical for CSR in vivo by suppressing large deletions within the Igh locus. Synopsis The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. Shld2−/− primary B‐cells have impaired ex vivo and in vivo CSR.A significant and heretofore undescribed $ Ig^{lo} $ population presents during CSR in Shieldin‐ and other DNA repair‐deficient B‐cells.$ Ig^{lo} $ cells are Ig‐negative as a result of hyper‐resection into the donor Ig constant region. Graphical Abstract The recently described Shieldin complex inhibits DNA resection. This study shows that Shieldin deficiency rescues BrcaΔ11 embryonic lethality and impairs class switch recombination in primary B‐cells through loss of immunoglobulin coding sequence as a result of enhanced DNA resection. © The Author(s) 2020 |
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SHLD2 promotes class switch recombination by preventing inactivating deletions within the Igh locus |
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https://dx.doi.org/10.15252/embr.201949823 |
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Munro, Meagan Chaudhary, Natasha Li, Conglei Berru, Maribel Wu, Brendan Durocher, Daniel Martin, Alberto |
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| score |
7.402669 |