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ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage-dependent manner. haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of enhances intestinal tumorigenesis in mice and the growth of human colorectal cancer xenografts. deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution. Chromosome instability (CIN) is a hallmark of cancer. We identify deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal as a major caretaker tumor suppressor gene..

The properties and structures of viruses are directly related to the three-dimensional structure of their capsid proteins,w hich arises from ac ombination of hydrophobic and supramolecular interactions,such as hydrogen bonds.The design of synthetic materials demonstrating similar synergistic interactions still remains ac hallenge.H erein, we report the synthesis of ap olymer/cyclic peptide conjugate that combines the capability to form supramolecular nanotubes via hydrogen bonds with the properties of an amphiphilic blockcopolymer. The analysis of aqueous solutions by scattering and imaging techniques revealed ab arrel-shaped alignment of single peptide nanotubes into al arge tubisome (length:2 60 nm (from SANS)) with ahydrophobic core (diameter:16nm) and ahydrophilic shell. These systems,which have astructure that is similar to those of viruses,w ere tested in vitro to elucidate their activity on cells.Remarkably,the rigid tubisomes are able to perforate the lysosomal membrane in cells and release asmall molecule into the cytosol.