The Controversial Roles of ADP-Ribosyl Hydrolases MACROD1, MACROD2 and TARG1 in Carcinogenesis

Abstract

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.

Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site

“…This gene spans more than 2 Mb and constitutes a common fragile site contributing to increased genomic instability. 24,25 Our results report intronic integration sites in the MACROD2 gene yet there is still lack of evidence concerning the functional consequence of these intronic integrations within MACROD2. Functional analyses are not straightforward due to the high rate of splicing in MACROD2 and the important number of alternative transcripts (coding and non-coding) of variable size.…”

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

“…Another role suggested for MACROD2 is in the DNA damage response [ 52 ] with ATM (ATM serine/threonine kinase) DNA repair kinase controlling the shuttling of MACROD2 between the cytoplasm and nucleus. Interestingly, deregulation of both MACROD1 and MACROD2 has also potentially been linked to cancer [ 53 , 54 , 55 ], although the validity of this has been queried [ 56 ]. Another suggested biological target of MACROD2 includes glycogen synthase kinase 3β (GSK3β), which is involved in WNT-signalling [ 25 ].…”

ADP-ribosylhydrolases: from DNA damage repair to COVID-19

“…Similarly, MacroD1 and MacroD2 also favor removal of MARylation over PARylation (Fig. 1) (Rack et al, 2016;Feijs et al, 2020). However, similar to PARG, all these enzymes play important roles in DNA damage repair.…”

“…PARG is recruited to DNA lesions for dePARylation, but leaves MARylation at DNA lesions. Thus, TARG1, MacroD1, and MacroD2 may act downstream of PARG for removal of the remaining MARylation at sites of DNA damage ( Bütepage et al, 2015 ; Feijs et al, 2020 ). Collectively, these macrodomains are key enzymatic domains in human ADP-ribosylhydrolases, and may act together to orchestrate deADP-ribosylation during DNA damage repair.…”