Meyer Ralph G, Meyer-Ficca Mirella L, Whatcott Clifford J, Jacobson Elaine L, Jacobson Myron K
Department of Animal Biology and Mari Lowe Center for Comparative Oncology, University of Pennsylvania, Kennett Square, PA 19348, USA.
Exp Cell Res. 2007 Aug 1;313(13):2920-36. doi: 10.1016/j.yexcr.2007.03.043. Epub 2007 Apr 19.
Poly(ADP-ribose)glycohydrolase (PARG) is the major enzyme capable of rapidly hydrolyzing poly(ADP-ribose) (PAR) formed by the diverse members of the PARP enzyme family. This study presents an alternative splice mechanism by which two novel PARG protein isoforms of 60 kDa and 55 kDa are expressed from the human PARG gene, termed hPARG60 and hPARG55, respectively. Homologous forms were found in the mouse (mPARG63 and mPARG58) supporting the hypothesis that expression of small PARG isoforms is conserved among mammals. A PARG protein of approximately 60 kDa has been described for decades but with its genetic basis unknown, it was hypothesized to be a product of posttranslational cleavage of larger PARG isoforms. While this is not excluded entirely, isolation and expression of cDNA clones from different sources of RNA indicate that alternative splicing leads to expression of a catalytically active hPARG60 in multiple cell compartments. A second enzyme, hPARG55, that can be expressed through alternative translation initiation from hPARG60 transcripts is strictly targeted to the mitochondria. Functional studies of a mitochondrial targeting signal (MTS) in PARG exon IV suggest that hPARG60 may be capable of shuttling between nucleus and mitochondria, which would be in line with a proposed function of PAR in genotoxic stress-dependent, nuclear-mitochondrial crosstalk.
聚（ADP-核糖）糖水解酶（PARG）是一种主要的酶，能够快速水解由PARP酶家族的不同成员形成的聚（ADP-核糖）（PAR）。本研究提出了一种可变剪接机制，通过该机制，从人PARG基因分别表达出两种新型的60 kDa和55 kDa的PARG蛋白异构体，分别称为hPARG60和hPARG55。在小鼠中发现了同源形式（mPARG63和mPARG58），这支持了小PARG异构体的表达在哺乳动物中保守的假设。一种约60 kDa的PARG蛋白已经被描述了几十年，但由于其遗传基础未知，曾被假设为较大PARG异构体的翻译后切割产物。虽然这并未被完全排除，但从不同RNA来源分离和表达cDNA克隆表明，可变剪接导致催化活性的hPARG60在多个细胞区室中表达。第二种酶hPARG55可通过从hPARG60转录本的可变翻译起始而表达，它严格定位于线粒体。对PARG外显子IV中线粒体靶向信号（MTS）的功能研究表明，hPARG60可能能够在细胞核和线粒体之间穿梭，这与PAR在基因毒性应激依赖性核-线粒体串扰中提出的功能一致。
