Masutani Mitsuko, Nakagama Hitoshi, Sugimura Takashi
Biochemistry Division, National Cancer Center Research Institute, Tokyo, Japan.
Genes Chromosomes Cancer. 2003 Dec;38(4):339-48. doi: 10.1002/gcc.10250.
Poly(ADP-ribose) and poly(ADP-ribose) polymerase (PARP) were discovered about 40 years ago, but their significance was not well elucidated until recently. In the early stage of the history of PARP, the presence of antibodies in the sera of human patients with lupus erythematosus indicated its natural occurrence. PARP, as well as the degrading enzyme, poly(ADP-ribose) glycohydrolase (PARG), are present in most eukaryotes except for yeasts. Studies that used inhibitors of PARP indicated the involvement of PARP and poly(ADP-ribose) in DNA damage repair, and eventually PARP was purified and the gene was cloned. Molecular analysis then revealed various functional domains, such as the one for binding to strand breaks of DNA. Parp-1-deficient and Parg-deficient cells showed, in general, enhanced sensitivity to the lethal effects of ionizing radiation and alkylating agents. Parp-1 knockout mouse embryonic stem cells developed into teratocarcinoma-like tumors when injected subcutaneously into nude mice, these tumors featuring giant cells similar to syncytiotrophoblastic giant cells with hyperploidy. Parp-1 was also found in centrosomes, suggesting that poly(ADP-ribose) and PARP-1 are functionally involved in the maintenance of chromatin structure and the equal distribution of chromosomes into daughter cells. Intriguing findings on the real biological significance continue to be generated, with new light shed on mechanisms of carcinogenesis and pointing to novel cancer treatments. Highlights during the last four decades of studies by laboratories focusing on poly(ADP-ribose)/PARP, including our own, are condensed and summarized in this review.
聚（ADP - 核糖）和聚（ADP - 核糖）聚合酶（PARP）是大约40年前被发现的，但直到最近它们的重要性才得到充分阐明。在PARP研究历史的早期，红斑狼疮患者血清中抗体的存在表明了它的天然存在。除酵母外，PARP以及降解酶聚（ADP - 核糖）糖苷水解酶（PARG）存在于大多数真核生物中。使用PARP抑制剂的研究表明PARP和聚（ADP - 核糖）参与DNA损伤修复，最终PARP被纯化并克隆了基因。随后的分子分析揭示了各种功能结构域，例如与DNA链断裂结合的结构域。一般来说，Parp - 1缺陷型和Parg缺陷型细胞对电离辐射和烷化剂的致死作用表现出更高的敏感性。将Parp - 1基因敲除的小鼠胚胎干细胞皮下注射到裸鼠体内后会发展成畸胎瘤样肿瘤，这些肿瘤具有类似于合体滋养层巨细胞的巨型细胞且染色体数目增多。在中心体中也发现了Parp - 1，这表明聚（ADP - 核糖）和PARP - 1在维持染色质结构以及染色体向子细胞的均匀分配中发挥功能作用。关于其真正生物学意义的有趣发现不断涌现，为癌症发生机制带来了新的启示，并指向新的癌症治疗方法。本综述总结了包括我们自己实验室在内的众多专注于聚（ADP - 核糖）/PARP研究的实验室在过去四十年中的研究亮点。
