HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression
Summary: B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at the donor and acceptor switch (S) regions. We show that the RNA-binding protein HNRNPU promotes C-NH...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723002954 |
| _version_ | 1797866921245278208 |
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| author | Ahmed M. Refaat Mikiyo Nakata Afzal Husain Hidetaka Kosako Tasuku Honjo Nasim A. Begum |
| author_facet | Ahmed M. Refaat Mikiyo Nakata Afzal Husain Hidetaka Kosako Tasuku Honjo Nasim A. Begum |
| author_sort | Ahmed M. Refaat |
| collection | DOAJ |
| description | Summary: B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at the donor and acceptor switch (S) regions. We show that the RNA-binding protein HNRNPU promotes C-NHEJ-mediated S-S joining through the 53BP1-shieldin DNA-repair complex. Notably, HNRNPU binds to the S region RNA/DNA G-quadruplexes, contributing to regulating R-loop and single-stranded DNA (ssDNA) accumulation. HNRNPU is an intrinsically disordered protein that interacts with both C-NHEJ and R-loop complexes in an RNA-dependent manner. Strikingly, recruitment of HNRNPU and the C-NHEJ factors is highly sensitive to liquid-liquid phase separation inhibitors, suggestive of DNA-repair condensate formation. We propose that HNRNPU facilitates CSR by forming and stabilizing the C-NHEJ ribonucleoprotein complex and preventing excessive R-loop accumulation, which otherwise would cause persistent DNA breaks and aberrant DNA repair, leading to genomic instability. |
| first_indexed | 2024-04-09T23:33:08Z |
| format | Article |
| id | doaj.art-9523c03dca4c4a5cb2f38c653370c63d |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T23:33:08Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-9523c03dca4c4a5cb2f38c653370c63d2023-03-21T04:16:18ZengElsevierCell Reports2211-12472023-03-01423112284HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppressionAhmed M. Refaat0Mikiyo Nakata1Afzal Husain2Hidetaka Kosako3Tasuku Honjo4Nasim A. Begum5Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, EgyptDepartment of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, JapanDepartment of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh 202002, IndiaDivision of Cell Signaling, Institute of Advanced Medical Sciences, University of Tokushima, Tokushima 770-8503, JapanDepartment of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan; Corresponding authorDepartment of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, JapanSummary: B cells generate functionally different classes of antibodies through class-switch recombination (CSR), which requires classical non-homologous end joining (C-NHEJ) to join the DNA breaks at the donor and acceptor switch (S) regions. We show that the RNA-binding protein HNRNPU promotes C-NHEJ-mediated S-S joining through the 53BP1-shieldin DNA-repair complex. Notably, HNRNPU binds to the S region RNA/DNA G-quadruplexes, contributing to regulating R-loop and single-stranded DNA (ssDNA) accumulation. HNRNPU is an intrinsically disordered protein that interacts with both C-NHEJ and R-loop complexes in an RNA-dependent manner. Strikingly, recruitment of HNRNPU and the C-NHEJ factors is highly sensitive to liquid-liquid phase separation inhibitors, suggestive of DNA-repair condensate formation. We propose that HNRNPU facilitates CSR by forming and stabilizing the C-NHEJ ribonucleoprotein complex and preventing excessive R-loop accumulation, which otherwise would cause persistent DNA breaks and aberrant DNA repair, leading to genomic instability.http://www.sciencedirect.com/science/article/pii/S2211124723002954CP: Molecular biologyCP: Immunology |
| spellingShingle | Ahmed M. Refaat Mikiyo Nakata Afzal Husain Hidetaka Kosako Tasuku Honjo Nasim A. Begum HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression Cell Reports CP: Molecular biology CP: Immunology |
| title | HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression |
| title_full | HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression |
| title_fullStr | HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression |
| title_full_unstemmed | HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression |
| title_short | HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression |
| title_sort | hnrnpu facilitates antibody class switch recombination through c nhej promotion and r loop suppression |
| topic | CP: Molecular biology CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723002954 |
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