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.

Bioinformatics Unit Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Department of Biology Faculty of Medicine Masaryk University Brno Czechia

Institute for Liver and Digestive Health Division of Medicine University College London London United Kingdom

International Clinical Research Center St Anne's University Hospital Brno Czechia

Zobrazit více v PubMed

Anney R., Klei L., Pinto D., Regan R., Conroy J., Magalhaes T. R., et al. (2010). A genome-wide scan for common alleles affecting risk for autism. Hum. Mol. Genet. 19 4072–4082. 10.1093/hmg/ddq307 PubMed DOI PMC

Bai P. (2015). Biology of poly (ADP-ribose) polymerases: the factotums of cell maintenance. Mol. Cell 58 947–958. 10.1016/j.molcel.2015.01.034 PubMed DOI

Barkauskaite E., Jankevicius G., Ahel I. (2015). structures and mechanisms of enzymes employed in the synthesis and degradation of PARP-dependent protein ADP-ribosylation. Mol. Cell 58 935–946. 10.1016/j.molcel.2015.05.007 PubMed DOI

Belenky P., Bogan K. L., Brenner C. (2007). NAD+ metabolism in health and disease. Trends Biochem. Sci. 32 12–19. 10.1016/j.tibs.2006.11.006 PubMed DOI

Benegiamo G., Vinciguerra M., Mazzoccoli G., Piepoli A., Andriulli A., Pazienza V. (2012). DNA methyltransferases 1 and 3b expression in Huh-7 cells expressing HCV core protein of different genotypes. Dig. Dis. Sci. 57 1598–1603. 10.1007/s10620-012-2160-1 PubMed DOI

Berulava T., Horsthemke B. (2010). The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels. Eur. J. Hum. Genet. 18 1054–1056. 10.1038/ejhg.2010.71 PubMed DOI PMC

Borghesan M., Fusilli C., Rappa F., Panebianco C., Rizzo G., Oben J. A., et al. (2016). DNA hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Res. 76 594–606. 10.1158/0008-5472.CAN-15-1336 PubMed DOI PMC

Bradley W. E., Raelson J. V., Dubois D. Y., Godin E., Fournier H., Prive C., et al. (2010). Hotspots of large rare deletions in the human genome. PLoS One 5:e9401. 10.1371/journal.pone.0009401 PubMed DOI PMC

Briffa R., Um I., Faratian D., Zhou Y., Turnbull A. K., Langdon S. P., et al. (2015). Multi-Scale genomic, transcriptomic and proteomic analysis of colorectal cancer cell lines to identify novel biomarkers. PLoS One 10:e0144708. 10.1371/journal.pone.0144708 PubMed DOI PMC

Chang Y. C., Hee S. W., Lee W. J., Li H. Y., Chang T. J., Lin M. W., et al. (2018). Genome-wide scan for circulating vascular adhesion protein-1 levels: macrod2 as a potential transcriptional regulator of adipogenesis. J. Diabetes Investig. 9 1067–1074. 10.1111/jdi.12805 PubMed DOI PMC

Chen J. A., Penagarikano O., Belgard T. G., Swarup V., Geschwind D. H. (2015). The emerging picture of autism spectrum disorder: genetics and pathology. Annu. Rev. Pathol. 10 111–144. 10.1146/annurev-pathol-012414-040405 PubMed DOI

Cheng Y., Quinn J. F., Weiss L. A. (2013). An eQTL mapping approach reveals that rare variants in the SEMA5A regulatory network impact autism risk. Hum. Mol. Genet. 22 2960–2972. 10.1093/hmg/ddt150 PubMed DOI PMC

Chorev M., Carmel L. (2012). The function of introns. Front. Genet. 3:55 10.3389/fgene.2012.00055 PubMed DOI PMC

Cohen M. S., Chang P. (2018). Insights into the biogenesis, function, and regulation of ADP-ribosylation. Nat. Chem. Biol. 14 236–243. 10.1038/nchembio.2568 PubMed DOI PMC

Di Biase S., Shim H. S., Kim K. H., Vinciguerra M., Rappa F., Wei M., et al. (2017). Fasting regulates EGR1 and protects from glucose- and dexamethasone-dependent sensitization to chemotherapy. PLoS Biol. 15:e2001951. 10.1371/journal.pbio.2001951 PubMed DOI PMC

Golia B., Moeller G. K., Jankevicius G., Schmidt A., Hegele A., Preisser J., et al. (2017). ATM induces macrod2 nuclear export upon DNA damage. Nucleic Acids Res. 45 244–254. 10.1093/nar/gkw904 PubMed DOI PMC

Hu N., Kadota M., Liu H., Abnet C. C., Su H., Wu H., et al. (2016). Genomic landscape of somatic alterations in esophageal squamous cell carcinoma and gastric cancer. Cancer Res. 76 1714–1723. 10.1158/0008-5472.CAN-15-0338 PubMed DOI PMC

Jahanshad N., Rajagopalan P., Hua X., Hibar D. P., Nir T. M., Toga A. W., et al. (2013). Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity. Proc. Natl. Acad. Sci. U.S.A. 110 4768–4773. 10.1073/pnas.1216206110 PubMed DOI PMC

Jankevicius G., Hassler M., Golia B., Rybin V., Zacharias M., Timinszky G., et al. (2013). A family of macrodomain proteins reverses cellular mono-ADP-ribosylation. Nat. Struct. Mol. Biol. 20 508–514. 10.1038/nsmb.2523 PubMed DOI PMC

Jones R. M., Cadby G., Blangero J., Abraham L. J., Whitehouse A. J. O., Moses E. K. (2014). MACROD2 gene associated with autistic-like traits in a general population sample. Psychiatr. Genet. 24 241–248. 10.1097/YPG.0000000000000052 PubMed DOI PMC

Kuniba H., Tsuda M., Nakashima M., Miura S., Miyake N., Kondoh T., et al. (2008). Lack of C20orf133 and FLRT3 mutations in 43 patients with Kabuki syndrome in Japan. J. Med. Genet. 45 479–480. 10.1136/jmg.2008.058503 PubMed DOI

Lee Y., Gamazon E. R., Rebman E., Lee Y., Lee S., Dolan M. E., et al. (2012). Variants affecting exon skipping contribute to complex traits. PLoS Genet. 8:e1002998. 10.1371/journal.pgen.1002998 PubMed DOI PMC

Linnebacher M., Ostwald C., Koczan D., Salem T., Schneider B., Krohn M., et al. (2013). Single nucleotide polymorphism array analysis of microsatellite-stable, diploid/near-diploid colorectal carcinomas without the CpG island methylator phenotype. Oncol. Lett. 5 173–178. 10.3892/ol.2012.1006 PubMed DOI PMC

Lionel A. C., Crosbie J., Barbosa N., Goodale T., Thiruvahindrapuram B., Rickaby J., et al. (2011). Rare copy number variation discovery and cross-disorder comparisons identify risk genes for ADHD. Sci. Transl. Med. 3:95ra75. 10.1126/scitranslmed.3002464 PubMed DOI

Maas N. M., Van De Putte T., Melotte C., Francis A., Schrander-Stumpel C. T., Sanlaville D., et al. (2007). The C20orf133 gene is disrupted in a patient with Kabuki syndrome. J. Med. Genet. 44 562–569. 10.1136/jmg.2007.049510 PubMed DOI PMC

Mohseni M., Cidado J., Croessmann S., Cravero K., Cimino-Mathews A., Wong H. Y., et al. (2014). MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers. Proc. Natl. Acad. Sci. U.S.A. 111 17606–17611. 10.1073/pnas.1408650111 PubMed DOI PMC

Murani E., Ponsuksili S., Seyfert H. M., Shi X., Wimmers K. (2009). Dual effect of a single nucleotide polymorphism in the first intron of the porcine secreted phosphoprotein 1 gene: allele-specific binding of C/EBP beta and activation of aberrant splicing. BMC Mol. Biol. 10:96. 10.1186/1471-2199-10-96 PubMed DOI PMC

Pazienza V., Panebianco C., Rappa F., Memoli D., Borghesan M., Cannito S., et al. (2016). Histone macroH2A1.2 promotes metabolic health and leanness by inhibiting adipogenesis. Epigenetics Chromatin 9:45. PubMed PMC

Perlis R. H., Ruderfer D., Hamilton S. P., Ernst C. (2012). Copy number variation in subjects with major depressive disorder who attempted suicide. PLoS One 7:e46315. 10.1371/journal.pone.0046315 PubMed DOI PMC

Rosenthal F., Feijs K. L., Frugier E., Bonalli M., Forst A. H., Imhof R., et al. (2013). Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases. Nat. Struct. Mol. Biol. 20 502–507. 10.1038/nsmb.2521 PubMed DOI

Sakthianandeswaren A., Parsons M. J., Mouradov D., Mackinnon R. N., Catimel B., Liu S., et al. (2018). Macrod2 haploin sufficiency impairs catalytic activity of PARP1 and Promotes chromosome instability and growth of intestinal tumors. Cancer Discov. 8 988–1005. 10.1158/2159-8290.CD-17-0909 PubMed DOI

Sheedfar F., Vermeer M., Pazienza V., Villarroya J., Rappa F., Cappello F., et al. (2015). Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet. Int. J. Obes. 39 331–338. 10.1038/ijo.2014.91 PubMed DOI

Tsang K. M., Croen L. A., Torres A. R., Kharrazi M., Delorenze G. N., Windham G. C., et al. (2013). A genome-wide survey of transgenerational genetic effects in autism. PLoS One 8:e76978. 10.1371/journal.pone.0076978 PubMed DOI PMC

Valenzuela D. M., Murphy A. J., Frendewey D., Gale N. W., Economides A. N., Auerbach W., et al. (2003). High-throughput engineering of the mouse genome coupled with high-resolution expression analysis. Nat. Biotechnol. 21 652–659. 10.1038/nbt822 PubMed DOI

van den Broek E., Den Uil S. H., Coupe V. M. H., Delis-Van Diemen P. M., Bolijn A. S., Bril H., et al. (2018). MACROD2 expression predicts response to 5-FU-based chemotherapy in stage III colon cancer. Oncotarget 9 29445–29452. 10.18632/oncotarget.25655 PubMed DOI PMC

van den Broek E., Dijkstra M. J., Krijgsman O., Sie D., Haan J. C., Traets J. J., et al. (2015). High prevalence and clinical relevance of genes affected by chromosomal breaks in colorectal cancer. PLoS One 10:e0138141. 10.1371/journal.pone.0138141 PubMed DOI PMC

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant