Role of R-loop in antibody class switching and B cell lymphomagenesis

R 环在抗体类别转换和 B 细胞淋巴瘤发生中的作用

• 批准号: 21K06015
• 负责人: Begum NasimAra
• 金额: $ 2.66万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2021
• 资助国家: 日本
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-21K06015/
• 关键词: CSR; R-loop; AID; HNRNPU; DNA Repair; NHEJ; B Cells; Genomic Instability; B cell

We successfully identified HNRNPU as a critical modulator of the R-loop in the IgH and cMyc loci. We confirmed that S-S recombination was impaired in the absence of HNRNPU due to C-NHEJ-mediated repair defect. HNRNPU is required for both CSR and aberrant chromosomal translocation in B cells. Key new findings are summarized below_(1) Mechanistic study indicates that HNRNPU functions as an R-loop suppressing factor, possibly through binding to the germline transcript (GLT) derived from the IgH locus. (2) Another line of evidence suggests that this binding to GLT depends on HNRNPU’s C-terminal, which explicitly recognizes the G-quadruplex structure.(3) RNase A treatment also dissociates HNRNPU from 53BP1 and Shileldn, suggesting HNRNPU stabilizes the C-NHEJ complex through RNA.

我们成功地鉴定了HNRNPU作为IgH和cMyc基因座中R环的关键调节剂。我们证实，由于C-NHEJ介导的修复缺陷，在HNRNPU不存在的情况下，S-S重组受损。HNRNPU是B细胞中CSR和异常染色体易位所必需的。（1）机制研究表明HNRNPU可能通过与IgH基因座衍生的生殖系转录本（GLT）结合而发挥R环抑制因子的作用。(2)另一系列证据表明，这种与GLT的结合依赖于HNRNPU的C-末端，其明确识别G-四链体结构。(3)RNase A处理还使HNRNPU与53 BP 1和Shileldn解离，表明HNRNPU通过RNA稳定C-NHEJ复合物。

项目成果

XLID syndrome gene Med12 promotes Ig isotype switching through chromatin modification and enhancer RNA regulation.

• DOI: 10.1126/sciadv.add1466
• 发表时间: 2022-11-25
• 期刊: Science advances
• 影响因子: 13.6

HNRNPU facilitates antibody class-switch recombination through C-NHEJ promotion and R-loop suppression

• DOI: 10.1016/j.celrep.2023.112284
• 发表时间: 2023-03-20
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Refaat，Ahmed M.;Nakata，Mikiyo;Begum，Nasim A.
• 通讯作者: Begum，Nasim A.

The Role of Mediator in Class Switch Recombination

中介者在类切换重组中的作用

• 发表时间: 2022
• 作者: Farazul Haque;Tasuku Honjo;Nasim A. Begum
• 通讯作者: Nasim A. Begum