Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To efficiently duplicate their genomic content, cells must overcome DNA lesions that interfere with processive DNA replication. These lesions may be removed and repaired, rather than just tolerated, to allow continuity of DNA replication on an undamaged DNA template. However, it is unclear how this is achieved at a molecular level. Here we identify a new replication-associated factor, ZRANB3 (zinc finger, RAN-binding domain containing 3), and propose its role in the repair of replication-blocking lesions. ZRANB3 has a unique structure-specific endonuclease activity, which is coupled to ATP hydrolysis. It cleaves branched DNA structures with unusual polarity, generating an accessible 3'-OH group in the template of the leading strand. Furthermore, ZRANB3 localizes to DNA replication sites and interacts with the components of the replication machinery. It is recruited to damaged replication forks via multiple mechanisms, which involve interactions with PCNA, K63-polyubiquitin chains, and branched DNA structures. Collectively, our data support a role for ZRANB3 in the replication stress response and suggest new insights into how DNA repair is coordinated with DNA replication to maintain genome stability.
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PMID:ZRANB3 is a structure-specific ATP-dependent endonuclease involved in replication stress response. 2288 22

Ubiquitin (Ub) is a vital regulatory component in various cellular processes, including cellular responses to viral infection. As obligate intracellular pathogens, viruses have the capacity to manipulate the ubiquitin (Ub) cycle to their advantage by encoding Ub-modifying proteins including deubiquitinases (DUBs). However, how cellular DUBs modulate specific viral infections, such as norovirus, is poorly understood. To examine the role of DUBs during norovirus infection, we used WP1130, a small molecule inhibitor of a subset of cellular DUBs. Replication of murine norovirus in murine macrophages and the human norovirus Norwalk virus in a replicon system were significantly inhibited by WP1130. Chemical proteomics identified the cellular DUB USP14 as a target of WP1130 in murine macrophages, and pharmacologic inhibition or siRNA-mediated knockdown of USP14 inhibited murine norovirus infection. USP14 is a proteasome-associated DUB that also binds to inositol-requiring enzyme 1 (IRE1), a critical mediator of the unfolded protein response (UPR). WP1130 treatment of murine macrophages did not alter proteasome activity but activated the X-box binding protein-1 (XBP-1) through an IRE1-dependent mechanism. In addition, WP1130 treatment or induction of the UPR also reduced infection of other RNA viruses including encephalomyocarditis virus, Sindbis virus, and La Crosse virus but not vesicular stomatitis virus. Pharmacologic inhibition of the IRE1 endonuclease activity partially rescued the antiviral effect of WP1130. Taken together, our studies support a model whereby induction of the UPR through cellular DUB inhibition blocks specific viral infections, and suggest that cellular DUBs and the UPR represent novel targets for future development of broad spectrum antiviral therapies.
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PMID:Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response. 2279 64

Enzymatic effectors targeting nucleic acids, proteins and other cellular components are the mainstay of conflicts across life forms. Using comparative genomics we identify a large class of eukaryotic proteins, which include effectors from oomycetes, fungi and other parasites. The majority of these proteins have a characteristic domain architecture with one of several N-terminal 'Header' domains, which are predicted to play a role in trafficking of these effectors, including a novel version of the Ubiquitin fold. The Headers are followed by one or more diverse C-terminal domains, such as restriction endonuclease (REase), protein kinase, HNH endonuclease, LK-nuclease (a RNase) and multiple distinct peptidase domains, which are predicted to carry their toxicity determinants. The most common types of these proteins appear to have originated from prokaryotic transposases (e.g. TN7 and Mu) and combine a CDC6/ORC1-STAND clade NTPase domain with a C-terminal REase domain. Other than the so-called Crinkler effectors of oomycetes and fungi, these effectors are encoded by other eukaryotic parasites such as trypanosomatids (the RHS proteins) and the rhizarian Plasmodiophora, and symbionts like Capsaspora Remarkably, we also find these proteins in free-living eukaryotes, including several viridiplantae, fungi, amoebozoans and animals. These versions might either still be transposons or function in other poorly understood eukaryote-specific inter-organismal and inter-genomic conflicts. These include the Medea1 selfish element of Tribolium that spreads via post-zygotic killing. We present a unified mechanism for the recombination-dependent diversification and action of this widespread class of molecular weaponry deployed across diverse conflicts ranging from parasitic to free-living forms.
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PMID:Transposons to toxins: the provenance, architecture and diversification of a widespread class of eukaryotic effectors. 2706 Jan 43

Well-studied structural motifs in Rad23 have been shown to bind polyubiquitin chains and the proteasome. These domains are predicted to enable Rad23 to transport polyubiquitylated (polyUb) substrates to the proteasome (Chen and Madura, 2002 [1]). The validation of this model, however, has been hindered by the lack of specific physiological substrates of Rad23. We report here that Rad23 can bind Ho-endonuclease (Ho-endo), a nuclear protein that initiates mating-type switching in Saccharomyces cerevisiae. We observed that the degradation of Ho-endo required export from the nucleus, in agreement with a previous report (Kaplun et al., 2003 [2]), and suggests that Rad23 can traffic proteins out of the nucleus. In agreement, the subcellular distribution of Rad23 is noticeably altered in genetic mutants that disrupt nucleocytoplasmic trafficking. Significantly, the location of Rad23 affected its binding to polyUb substrates. Mutations in nuclear export stabilized substrates, and caused accumulation in the nucleus. Importantly, Rad23 also accumulated in the nucleus in an export mutant, and bound to higher levels of polyUb proteins. In contrast, Rad23 is localized in the cytosol in rna1-1, a nucleocytoplasmic transport mutant, and it forms reduced binding to polyUb substrates. These and other studies indicate that substrates that are conjugated to polyubiquitin chains in the nucleus may rely on an export-dependent mechanism to be degraded by the proteasome. The evolutionary conservation of Rad23 and similar substrate-trafficking proteins predicts an important role for export in the turnover of nuclear proteins.
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PMID:The Cellular Location of Rad23, a Polyubiquitin Chain-Binding Protein, Plays a Key Role in Its Interaction with Substrates of the Proteasome. 3214 57