MACROD2 expression predicts response to 5-FU-based chemotherapy in stage III colon cancer

Broek, Egon van den; Uil, Sjoerd H. den; Coupé, Veerle M.H.; Diemen, Pien M. Delis-van; Bolijn, Anne S.; Bril, Herman; Stockmann, H. B. A. C.; Grieken, Nicole C.T. van; Meijer, Gerrit A.; Fijneman, Remond J.A.

doi:10.18632/oncotarget.25655

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…This nuclear export restricts the time that MACROD2 spend at the DNA lesions, which may decrease the net ADP-ribosylhydrolase activity at these sites of damage (Golia et al, 2017). Low expression of MACROD2 is associated with poor prognosis of colorectal cancer patients (van den Broek et al, 2018). A recent breakthrough report documented the generation of MACROD2 knock-out mice (obtained from the KOMP, Jackson Laboratory), which developed normally into adulthood and displayed significantly enhanced intestinal tumorigenesis in the ApcMin/+ susceptible genetic background (Sakthianandeswaren et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Heterozygous and homozygous depletion of MACROD2 enhanced significantly intestinal tumorigenesis in this susceptible genetic background (Sakthianandeswaren et al, 2018). Accordingly, at the clinical level, low nuclear expression of MACROD2 is associated with poor prognosis of patients with stage III primary colon cancer (van den Broek et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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

Mazza

Vinciguerra

2018

Front. Genet.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mazza

Vinciguerra

2018

Front. Genet.

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“…TMAs have been used in a range of human cancer investigations, including prostate cancer, 15,16 breast cancer, 7 and colon cancer. 8,17,18 The tumor bank within our Comprehensive Cancer Center has been actively collecting FFPE tumor and normal tissues from patients preoperatively consented to IRB-approved tissue procurement protocols to build an FFPE tissue bank to complement our long-standing frozen tissue bank. We have leveraged this resource to generate TMAs for cancer research.…”

Section: Discussionmentioning

confidence: 99%

Optimization of Tissue Microarrays from Banked Human Formalin-Fixed Paraffin Embedded Tissues in the Cancer Research Setting

Sexton

Kucera

Levine

et al. 2019

Biopreservation and Biobanking

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The tissue microarray (TMA) is a powerful tool for cancer biomarker discovery and validation. Tens to hundreds of samples can be evaluated simultaneously for molecular marker status at the protein or nucleic acid level. Although fully automated or semiautomated technologies for TMA creation provide excellent precision with respect to core transfer, they do not obviate the need for technical expertise to successfully generate highquality TMA blocks and derivative sections. We have leveraged our expanding bank of formalin-fixed paraffin embedded paired tumor and normal tissues in our academic cancer center to provide a rich source of input material for cancer research TMAs. In this study, we report a stepwise optimization of TMA generation parameters, including paraffin wax selection, tempering protocol, and sectioning conditions, to achieve the best ribbon sectioning.

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“…This latter antibody has been discontinued by the company. Despite the poor characterisation of this now retracted MACROD2 antibody, it has for example been used to correlate protein expression to response to chemotherapy in patients with colon cancer 49 . We listed all antibodies available and have found that either no whole blots are shown to demonstrate specificity or that unspecific bands are present ( Supplementary Table S1).…”

Section: Macrod1 Macrod2 and Targ1 Are Differentially Expressed Thementioning

confidence: 99%

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

Žaja

Aydin

Lippok

et al. 2020

Sci Rep

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The posttranslational modification ADP-ribosylation is involved in many cellular processes, with distinct roles for poly- and mono(ADP-ribosyl)ation (PAR- and MARylation, respectively). Reversibility of intracellular MARylation was demonstrated with the discovery of MACROD1, MACROD2 and TARG1, three macrodomain-containing enzymes capable of reversing MARylation of proteins and RNA. While the three enzymes have identical activities in vitro, their roles in cells are unclear and published data are partially contradictory, possibly due to a lack of validated reagents. We developed monoclonal antibodies to study these proteins and analysed their tissue distribution and intracellular localisation. MACROD1 is most prevalent in mitochondria of skeletal muscle, MACROD2 localises to nucleo- and cytoplasm and is found so far only in neuroblastoma cells, whereas the more ubiquitously expressed TARG1 is present in nucleoplasm, nucleolus and stress granules. Loss of MACROD1 or loss of TARG1 leads to disruption of mitochondrial or nucleolar morphology, respectively, hinting at their importance for these organelles. To start elucidating the underlying mechanisms, we have mapped their interactomes using BioID. The cellular localisation of interactors supports the mitochondrial, nucleolar and stress granule localisation of MACROD1 and TARG1, respectively. Gene ontology analysis suggests an involvement of MACROD1 and TARG1 in RNA metabolism in their respective compartments. The detailed description of the hydrolases’ expression, localisation and interactome presented here provides a solid basis for future work addressing their physiological function in more detail.

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MACROD2 expression predicts response to 5-FU-based chemotherapy in stage III colon cancer

Cited by 9 publications

References 20 publications

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

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

Optimization of Tissue Microarrays from Banked Human Formalin-Fixed Paraffin Embedded Tissues in the Cancer Research Setting

Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome

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