Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells
Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells
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DOI：
10.1073/pnas.1418947112
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发表时间：
2015-02-17
影响因子：
11.1
通讯作者：
Pan-Hammarstrom, Qiang
中科院分区：
文献类型：
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作者：
Bjorkman, Andrea;Qvist, Per;Pan-Hammarstrom, Qiang
乳腺癌1型易感蛋白（BRCA 1）具有多种功能，有助于基因组完整性和肿瘤抑制。它在同源重组（HR）过程中参与DNA双链断裂（DSB）的修复是公认的，而它在第二个主要的DSB修复途径，非同源末端连接（NHEJ）的参与，仍然存在争议。在这里，我们研究了BRCA 1在免疫球蛋白类别转换重组过程中转换（S）区域DSB修复中的作用，这是一种依赖于经典NHEJ机制的生理缺失/重组过程。在从BRCA 1缺陷型人B细胞扩增的重组连接处，观察到使用基于微同源性的替代性末端连接（A-EJ）和增加的S区内缺失频率以及反向S序列的插入。此外，在E3泛素蛋白连接酶RNF 168缺陷、范可尼贫血J组蛋白（FACJ、BRIP 1）缺陷或DNA内切核酸酶RBBP 8（CtIP）受损细胞的重组连接处发现长微同源性的使用增加，而在乳腺癌2型易感蛋白（BRCA 2）缺陷细胞中观察到S区倒位频率增加。因此，BRCA 1，连同其相互作用的合作伙伴，似乎发挥了重要的作用，修复DSB类转换重组过程中产生的促进经典NHEJ途径。这可能不仅提供了BRCA 1在维持基因组稳定性和肿瘤抑制中的功能的一般机制，而且还可能指出BRCA 1在B细胞淋巴瘤发生中的先前未被认识的作用。
Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of micro-homology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1' s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.