Details of UBR5 mutations observed in MCL and mutations reported in other cancers. (A) Top panel: intron-exon structure of UBR5 with Exon 58 highlighted in red. Bottom panel: details of deleterious mutations in the UBR5 gene are shown. All mutations are clustering within the genomic region of exon 58, the second last exon of the gene. The DNA sequence of exon 58 is indicated in bold. The chromatogram is showing a heterozygote 1-base pair deletion in MC122, the corresponding germline DNA sequence confirms this mutation as somatic alteration. (B) UBR5 protein structure with its ubiquitin-associated domain (UBA), UBR box (a zinc finger-like domain), polyadenylate-binding protein C terminus domain (PABC), and a C-terminal HECT domain. Mutations reported in other cancers²³  are present in lower frequency and scattered throughout the protein. Blue circles: missense mutations; red triangles: deleterious mutations. All deleterious mutations found in MCL cluster within the C-terminal part of the HECT domain, upstream of the conserved cysteine residue at amino acid position 2768. (C) Protein alignment of truncated UBR5 mutant versions predicting a loss of ubiquitin-binding and transfer function.