Mono-ADP-Ribosylhydrolase MACROD2 Is Dispensable for Murine Responses to Metabolic and Genotoxic Insults

Abstract

ADP-ribosylation is an important post-translational protein modification that regulates diverse biological processes, controlled by dedicated transferases, and hydrolases. Disruption in the gene encoding for MACROD2, a mono-ADP-ribosylhydrolase, has been associated to the Kabuki syndrome, a pediatric congenital disorder characterized by facial anomalies, and mental retardation. Non-coding and structural mutations/variations in MACROD2 have been associated to psychiatric disorders, to obesity, and to cancer. Mechanistically, it has been recently shown that frequent deletions of the MACROD2 alter DNA repair and sensitivity to DNA damage, resulting in chromosome instability, and colorectal tumorigenesis. Whether MACROD2 deletion sensitizes the organism to metabolic and tumorigenic stressors, in absence of other genetic drivers, is unclear. As MACROD2 is ubiquitously expressed in mice, here we generated constitutively whole-body knock-out mice for MACROD2, starting from mouse embryonic stem (ES) cells deleted for the gene using the VelociGene® technology, belonging to the Knockout Mouse Project (KOMP) repository, a NIH initiative. MACROD2 knock-out mice were viable and healthy, indistinguishable from wild type littermates. High-fat diet administration induced obesity, and glucose/insulin intolerance in mice independent of MACROD2 gene deletion. Moreover, sub-lethal irradiation did not indicate a survival or lethality bias in MACROD2 knock-out mice compared to wild type littermates. Altogether, our data point against a sufficient role of MACROD2 deletion in aggravating high-fat induced obesity and DNA damage-associated lethality, in absence of other genetic drivers.

Behavioural Characterisation of Macrod1 and Macrod2 Knockout Mice

“…All Macrod1 and Macrod2 KO mice were born at the expected Mendelian ratios. Protein deletion in these genetic models has been reported previously by us for Macrod1 [29] and by two other independent research groups for Macrod2 [53,72].…”

“…Since the IMPC do not usually keep mice beyond 16 weeks, it is highly likely they would not detect the increased hyperactivity with old age, or worsening gait. In terms of the IMPC metabolic defects, Lo Re et al were unable to confirm a role for Macrod2 in metabolism by glucose tolerance test, insulin tolerance test or in high fat diet induced obesity [ 72 ].…”

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

“…Non-coding and structural mutations/variations in the germline MACROD2 gene have been associated with psychiatric disorders, obesity and cancer predisposition. 18 – 20 Deletions in the MACROD2 gene are frequent in colorectal cancer 21 , 22 and are reported to alter DNA repair and sensitivity to DNA damage and consequently impact colorectal tumorigenesis. 23 Neither RNA expression nor functional studies support a tumour suppressor role of MACROD2 gene.…”

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

“…These findings appear paradoxical with the previous report, where loss of MACROD2 impairs cell growth from a loss of resistance to tamoxifen. MacroD2 knockout mice do not show altered survival rates after sub-lethal irradiation compared to wildtype mice, which indicates that loss of MACROD2 alone is not sufficient to drive tumourigenesis triggered by DNA damage [109]. It is not clear whether loss or overexpression of MACROD2 contributes to tumourigenesis, or whether both can drive tumour growth dependent on conditions, such as the functionality of the DNA damage repair systems or the oestrogen receptor status.…”