Institut National de la Santé et de la Recherche Médicale U768, Hôpital Necker Enfants Malades, 75015 Paris, France.
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22225-30. doi: 10.1073/pnas.1012591108. Epub 2010 Dec 6.
Ig class-switch recombination (CSR) is a region-specific process that exchanges the constant Ig heavy-chain region and thus modifies an antibody's effector function. DNA lesions in switch (S) regions are induced by activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2), subsequently processed to DNA breaks, and resolved by either the classical nonhomologous end-joining pathway or the alternative end-joining pathway (XRCC4/DNA ligase 4- and/or Ku70/Ku80-independent and prone to increased microhomology usage). We examined whether the induction of DNA lesions influences DNA end-joining during CSR by analyzing Sμ-Sα recombination junctions in various human Ig CSR defects of DNA lesion induction. We observed a progressive trend toward the usage of microhomology in Sμ-Sα recombination junctions from AID-heterozygous to AID-autosomal dominant to UNG2-deficient B lymphocytes. We thus hypothesize that impaired induction of DNA lesions in S regions during CSR leads to unusual end-processing of the DNA breaks, resulting in microhomology-mediated end-joining, which could be an indication for preferential processing by alternative end-joining rather than by classical nonhomologous end-joining.
免疫球蛋白类别转换重组（CSR）是一个区域特异性过程，它交换免疫球蛋白重链恒定区，从而改变抗体的效应功能。激活诱导胞嘧啶脱氨酶（AID）和尿嘧啶-DNA 糖基化酶 2（UNG2）在开关（S）区域诱导 DNA 损伤，随后被加工成 DNA 断裂，并通过经典的非同源末端连接途径或替代末端连接途径（不依赖 XRCC4/DNA 连接酶 4 和/或 Ku70/Ku80 且易于增加微同源性使用）进行解决。我们通过分析各种人 Ig CSR 缺陷中 DNA 损伤诱导的 Sμ-Sα 重组连接点，研究了 DNA 损伤的诱导是否影响 CSR 中的 DNA 末端连接。我们观察到，从 AID 杂合子到 AID 常染色体显性遗传再到 UNG2 缺陷 B 淋巴细胞，Sμ-Sα 重组连接点中微同源性的使用呈渐进趋势。因此，我们假设 CSR 过程中 S 区域中 DNA 损伤的诱导受损会导致 DNA 断裂的异常末端处理，导致微同源性介导的末端连接，这可能表明优先通过替代末端连接而不是经典的非同源末端连接进行处理。
