Feijs Karla L H, Cooper Christopher D O, Žaja Roko
Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Department of Biological and Geographical Sciences, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield West Yorkshire HD3 4AP, UK.
Cancers (Basel). 2020 Mar 5;12(3):604. doi: 10.3390/cancers12030604.
Post-translational modifications (PTM) of proteins are crucial for fine-tuning a cell's response to both intracellular and extracellular cues. ADP-ribosylation is a PTM, which occurs in two flavours: modification of a target with multiple ADP-ribose moieties (poly(ADP-ribosyl)ation or PARylation) or with only one unit (MARylation), which are added by the different enzymes of the PARP family (also known as the ARTD family). PARylation has been relatively well-studied, particularly in the DNA damage response. This has resulted in the development of PARP inhibitors such as olaparib, which are increasingly employed in cancer chemotherapeutic approaches. Despite the fact that the majority of PARP enzymes catalyse MARylation, MARylation is not as well understood as PARylation. MARylation is a dynamic process: the enzymes reversing intracellular MARylation of acidic amino acids (MACROD1, MACROD2, and TARG1) were discovered in 2013. Since then, however, little information has been published about their physiological function. MACROD1, MACROD2, and TARG1 have a 'macrodomain' harbouring the catalytic site, but no other domains have been identified. Despite the lack of information regarding their cellular roles, there are a number of studies linking them to cancer. However, some of these publications oppose each other, some rely on poorly-characterised antibodies, or on aberrant localisation of overexpressed rather than native protein. In this review, we critically assess the available literature on a role for the hydrolases in cancer and find that, currently, there is limited evidence for a role for MACROD1, MACROD2, or TARG1 in tumorigenesis.
蛋白质的翻译后修饰（PTM）对于微调细胞对细胞内和细胞外信号的反应至关重要。ADP-核糖基化是一种翻译后修饰，有两种形式：用多个ADP-核糖部分修饰靶标（多聚（ADP-核糖基）化或PARylation）或仅用一个单位修饰（单ADP-核糖基化或MARylation），这是由PARP家族（也称为ARTD家族）的不同酶添加的。PARylation已经得到了相对充分的研究，特别是在DNA损伤反应方面。这导致了PARP抑制剂如奥拉帕尼的开发，这些抑制剂越来越多地用于癌症化疗方法中。尽管大多数PARP酶催化单ADP-核糖基化，但单ADP-核糖基化的了解不如PARylation。单ADP-核糖基化是一个动态过程：2013年发现了逆转酸性氨基酸细胞内单ADP-核糖基化的酶（MACROD1、MACROD2和TARG1）。然而，从那时起，关于它们生理功能的信息很少发表。MACROD1、MACROD2和TARG1有一个包含催化位点的“宏观结构域”，但没有发现其他结构域。尽管缺乏关于它们细胞作用的信息，但有许多研究将它们与癌症联系起来。然而，其中一些出版物相互矛盾，一些依赖于特征不明确的抗体，或者依赖于过表达而非天然蛋白质的异常定位。在这篇综述中，我们批判性地评估了关于这些水解酶在癌症中作用的现有文献，发现目前，关于MACROD1、MACROD2或TARG1在肿瘤发生中的作用证据有限。
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