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  • Based on the similar activities

    2021-07-28

    Based on the similar activities of Rad6p and Cdc34p (i.e., both are E2 ub-conjugating enzymes) on ubiquitinylation of p33 replication protein, we propose that Rad6p and the plant Ubc2p mono- and bi-ubiquitinate the viral replication proteins in order to facilitate the recruitment of the cellular ESCRT proteins via binding to Vps23p (Tsg101 in mammals) ESCRT-I protein and Bro1p (ALIX in mammals) ESCRT-accessory protein (Barajas and Nagy, 2010). These events then lead to subversion of the cellular ESCRT machinery consisting of additional ESCRT-I and ESCRT-III components and Vps4p AAA+ ATPase (Barajas et al., 2009a, Barajas et al., 2014, Barajas and Nagy, 2010). These cellular ESCRT proteins are likely involved in membrane bending/invagination and viral spherule formation during the assembly of the membrane-bound tombusvirus replicase complexes (Barajas et al., 2009a, Barajas et al., 2014, Barajas and Nagy, 2010). In support of the above model, co-purification experiments showed that Rad6p is involved in promoting the subversion of Vps23p and Vps4p ESCRT proteins for viral replicase complex assembly. Protein ubiquitination and the ubiquitin proteosome system (UPS) sr9009 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 sr9009 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: 6.3.2.19) 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.