Genomic rearrangements are a hallmark of human cancers. Here, we identify the piggyBac transposable element derived 5 (PGBD5) gene as encoding an active DNA transposase expressed in the majority of childhood solid tumors, including lethal rhabdoid tumors. Using assembly-based whole-genome DNA sequencing, we found previously undefined genomic rearrangements in human rhabdoid tumors. These rearrangements involved PGBD5-specific signal (PSS) sequences at their breakpoints and recurrently inactivated tumor-suppressor genes. PGBD5 was physically associated with genomic PSS sequences that were also sufficient to mediate PGBD5-induced DNA rearrangements in rhabdoid tumor cells. Ectopic expression of PGBD5 in primary immortalized human cells was sufficient to promote cell transformation in vivo. This activity required specific catalytic residues in the PGBD5 transposase domain as well as end-joining DNA repair and induced structural rearrangements with PSS breakpoints. These results define PGBD5 as an oncogenic mutator and provide a plausible mechanism for site-specific DNA rearrangements in childhood and adult solid tumors.

中文翻译：

---

PGBD5促进人类肿瘤中的特定部位致癌突变

基因组重排是人类癌症的标志。在这里，我们确定piggyBac转座子衍生5（PGBD5）基因编码在大多数儿童实体瘤，包括致死性横纹肌瘤中表达的活性DNA转座酶。使用基于装配的全基因组DNA测序，我们发现了人类横纹肌瘤中以前未定义的基因组重排。这些重排涉及PGBD5特异性信号（PSS）序列在其断点处和反复失活的肿瘤抑制基因。PGBD5在物理上与基因组PSS序列相关，而PSS序列也足以在横纹肌瘤细胞中介导PGBD5诱导的DNA重排。PGBD5在永生的人类细胞中异位表达足以促进体内细胞转化。该活性需要PGBD5转座酶结构域中的特定催化残基以及末端连接的DNA修复和PSS断裂点诱导的结构重排。这些结果将PGBD5定义为致癌突变体，并为儿童和成人实体瘤中的位点特异性DNA重排提供了合理的机制。