Protein ubiquitination and the ubiquitin proteosome system
Protein ubiquitination and the ubiquitin proteosome system (UPS) play a role in many viral infections by targeting viral proteins for degradation or for modification that leads to altered viral protein functions (Alcaide-Loridan and Jupin, 2012, Okumura et al., 2006, Shackelford and Pagano, 2005). Viruses also usurp UPS to target host antiviral proteins for degradation to facilitate viral infections. Viral proteins could also reverse protein ubiquitination that likely regulate viral infections (Alcaide-Loridan and Jupin, 2012, Chenon et al., 2012, Lindner, 2007, Lombardi et al., 2013).
Materials and methods
Acknowledgments The authors thank to Dr. C. Boone (U. Toronto) for Cdc34 yeast. This work was supported by a grant for Overseas Researcher from Nihon University to Y. I. and by NSF (MCB 1122039) to PDN.
Main Text Fanconi anemia (FA) is a rare genetic disease characterized by genome instability, cancer predisposition, progressive bone marrow failure (BMF), and various developmental abnormalities that often include radial ray anomalies, short stature, and visceral malformations. FA Bryostatin 1 are hypersensitive to DNA interstrand crosslink damage (ICL) and various types of damage due to endogenous aldehydes.2, 3, 4, 5 FA is caused by mutations in any one of 16 genes that together comprise the FA pathway. These genes include FANCA (MIM: 617139), FANCB (MIM: 300515), FANCC (MIM: 613899), FANCD1 (BRCA2) (MIM: 600185), FANCD2 (MIM: 613984), FANCE (MIM: 613976), FANCF (MIM: 603467), FANCG (XRCC9) (MIM: 600901), FANCI (MIM: 611360), FANCJ (BRIP1) (MIM: 614082), FANCL (PHF9) (MIM: 614083), FANCN (PALB2) (MIM: 610832), FANCO (RAD51C) (MIM: 613390), FANCP (SLX4) (MIM: 613951), FANCQ (XPF) (MIM: 615272), and FANCS (BRCA1) (MIM: 113705). A recent study indicated that biallelic mutations in FA-related FANCM (MIM: 609644) do not cause an FA phenotype in humans, raising a concern whether this nomenclature is appropriate or not. In the upstream part of the pathway, the FA core E3 ligase complex consisting of eight gene products and other associated proteins monoubiquitinates FANCD2 and FANCI, resulting in chromatin accumulation/focus formation of FANCD2 that probably recognizes stalled replication forks upon ICL or aldehyde damage. This is the critical event that regulates recruitment of structure-specific nucleases and subsequent incision/unhooking of fork-blocking lesions, mobilizing the downstream repair pathway components.2, 3UBE2T (MIM: 610538) encodes an E2 ubiquitin conjugating enzyme (EC: 18.104.22.168) which has been implicated in this monoubiquitination reaction both in vivo7, 8, 9 and in vitro.10, 11, 12, 13 We previously analyzed the ALDH2 genotypes in 64 Japanese FA-affected individuals with the approval of the Research Ethics Committee of the Tokai University Hospital and Kyoto University and obtained informed consent from the families of all subjects involved. Our report included two case subjects in which mutations in the genes previously associated with FA were excluded by whole exome sequencing (WES) (listed as numbers 60 and 61 in Table S1 in Hira et al.) (Figure S1). Serendipitously, UBE2T mutations were found in both of them (Figures 1A–1C). The two persons are hereafter designated PNGS-252 (family 1-II-1 in Figure 1D) and PNGS-255 (family 2-II-1 in Figure 1D) (Table 1). They were from unrelated families (Figure 1D) living in different geographic locations in Japan. Both individuals displayed typical FA phenotypes, with malformations and hematological abnormalities that necessitated hematopoietic stem cell transplantation (Table 1; see Supplemental Data). Chromosome fragility in lymphocytes (described in Table S2 in Hira et al.) was consistent with the diagnosis of FA.