Mechanisms of oncogenic chromosomal translocations
Mechanisms of oncogenic chromosomal translocations
复制标题
DOI：
10.1111/nyas.12370
复制
发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Williamson, Elizabeth
中科院分区：
文献类型：
--
作者：
Byrne, Michael;Wray, Justin;Williamson, Elizabeth
染色体易位是由于异源染色体中两个DNA双链断裂(DSB)的不适当宗教引起的。这些DSB可由内源或外源产生。导致DSB易位的内源性来源包括免疫受体成熟过程中不适当的重组激活基因(RAG)或激活诱导的脱氨酶(AID)活性。内源性双链断裂也可以发生在非规范的DNA结构或折叠的复制叉处。导致易位的DSB的外源来源包括电离辐射(IR)和癌症化疗。异源染色体的空间接近对易位也很重要。虽然DNA DSB修复存在三种不同的途径，但越来越多的证据支持替代非同源末端连接(ANHEJ)是大多数易位发生的主要途径。由多聚ADP-核糖聚合酶1(PARP1)启动的aNHEJ在DNA DSB修复中的使用频率低于其他形式的DSB修复。我们最近发现，PARP1是染色体易位所必需的，已经在临床使用的小分子PARP1抑制剂可以抑制IR或拓扑异构酶II抑制所产生的易位。这些数据证实了PARP1在NHEJ介导的染色体易位中的中心作用，并增加了在继发性致癌染色体易位的高危患者中使用临床可用的PARP1抑制剂的可能性。
Chromosome translocations are caused by inappropriate religation of two DNA double-strand breaks (DSBs) in heterologous chromosomes. These DSBs can be generated by endogenous or exogenous sources. Endogenous sources of DSBs leading to translocations include inappropriate recombination activating gene (RAG) or activation-induced deaminase (AID) activity during immune receptor maturation. Endogenous DSBs can also occur at noncanonical DNA structures or at collapsed replication forks. Exogenous sources of DSBs leading to translocations include ionizing radiation (IR) and cancer chemotherapy. Spatial proximity of the heterologous chromosomes is also important for translocations. While three distinct pathways for DNA DSB repair exist, mounting evidence supports alternative nonhomologous end joining (aNHEJ) as the predominant pathway through which the majority of translocations occur. Initiated by poly (ADP-ribose) polymerase 1 (PARP1), aNHEJ is utilized less frequently in DNA DSB repair than other forms of DSB repair. We recently found that PARP1 is essential for chromosomal translocations to occur and that small molecule PARP1 inhibitors, already in clinical use, can inhibit translocations generated by IR or topoisomerase II inhibition. These data confirm the central role of PARP1 in aNHEJ-mediated chromosomal translocations and raise the possibility of using clinically available PARP1 inhibitors in patients who are at high risk for secondary oncogenic chromosomal translocations.