USC Norris Comprehensive Cancer Ctr, Rm. 5428 Departments of Pathology, Biochemistry & Molecular Biology, Molecular Microbiology & Immunology, and of Biological Sciences (Section of Molecular & Computational Biology), University of Southern California, Los Angeles, CA 90089-9176, USA.
BMC Genomics. 2010 Feb 10;11 Suppl 1(Suppl 1):S1. doi: 10.1186/1471-2164-11-S1-S1.
Many human cancers are associated with characteristic chromosomal rearrangements, especially hematopoietic cancers such as leukemias and lymphomas. The first and most critical step in the rearrangement process is the induction of two DNA double-strand breaks (DSB). In all cases, at least one of the two DSBs is generated by a pathologic process, such as (1) randomly-positioned breaks due to ionizing radiation, free radical oxidative damage, or spontaneous hydrolysis; (2) breaks associated with topoisomerase inhibitor treatment; or (3) breaks at direct or inverted repeat sequences, mediated by unidentified strand breakage mechanisms. In lymphoid cells, one of the two requisite DSBs is often physiologic, the result of V(D)J recombination or class switch recombination (CSR) at the lymphoid antigen receptor loci. The RAG complex, which causes the DSBs in V(D)J recombination, can cause (4) sequence-specific, pathologic DSBs at sites that fit the consensus of their normal V(D)J recombination signal targets; or (5) structure-specific, pathologic DSBs at regions of single- to double-strand transition. CSR occurs specifically in the B-cell lineage, and requires (6) activation-induced cytidine deaminase (AID) action at sites of single-stranded DNA, which may occur pathologically outside of the normal target loci of class switch recombination regions and somatic hypermutation (SHM) zones. Recent work proposes a seventh mechanism: the sequential action of AID and the RAG complex at CpG sites provides a coherent model for the pathologic DSBs at some of the most common sites of translocation in human lymphoma - the bcl-2 gene in follicular lymphoma and diffuse large B-cell lymphoma, and the bcl-1 gene in mantle cell lymphoma.
许多人类癌症都与特征性的染色体重排有关，尤其是血液系统癌症，如白血病和淋巴瘤。在重排过程中，第一个也是最关键的步骤是诱导两个 DNA 双链断裂（DSB）。在所有情况下，两个 DSB 中至少有一个是由病理过程产生的，例如：（1）由于电离辐射、自由基氧化损伤或自发水解导致随机位置的断裂；（2）与拓扑异构酶抑制剂治疗相关的断裂；（3）通过不明的链断裂机制，在直接或反向重复序列处发生的断裂。在淋巴细胞中，两个必需的 DSB 中的一个通常是生理性的，是淋巴细胞抗原受体基因座上 V(D)J 重组或类别转换重组（CSR）的结果。RAG 复合物在 V(D)J 重组中引起 DSB，它可以在符合其正常 V(D)J 重组信号靶的序列特异性病理性 DSB 处（4）；或在单链到双链转换区域的结构特异性病理性 DSB 处（5）。CSR 仅发生在 B 细胞谱系中，需要（6）激活诱导的胞嘧啶脱氨酶（AID）在单链 DNA 位点的作用，该作用可能在正常的类别转换重组区域和体细胞超突变（SHM）区之外的病理性靶位发生。最近的研究工作提出了第七种机制：AID 和 RAG 复合物在 CpG 位点的顺序作用为人类淋巴瘤中一些最常见的易位部位的病理性 DSB 提供了一个连贯的模型-滤泡性淋巴瘤和弥漫性大 B 细胞淋巴瘤中的 bcl-2 基因，以及套细胞淋巴瘤中的 bcl-1 基因。
