{"doi":"10.1101/2020.04.28.067074","title":"The phylogenetic functional conservation of <i>Drosophila</i> Seven-In-Absentia (SINA) E3 ligase and its two human paralogs, SIAH1 and SIAH2, in <i>Drosophila</i> eye development","abstract":"Abstract Seven-IN-Absentia (SINA) is the most downstream signaling gatekeeper identified thus far in the RAS/EGFR pathway that controls photoreceptor cell fate determination in Drosophila . Underscoring the central importance of SINA is its phylogenetic conservation in metazoans, with over 83% amino acid identities shared between Drosophila SINA and human SINA homologs (SIAHs). SIAH is a major tumor vulnerability in multidrug-resistant and incurable cancer. SIAH inhibition is an effective strategy to shut down the tumor-driving K-RAS/EGFR/HER2 pathway activation that promotes malignant tumor growth and metastatic dissemination. To further delineate the SINA function in the RAS/EGFR pathway, a genetic modifier screen was conducted, and 28 new sina mutant alleles were isolated via ethyl methanesulfonate (EMS) and X-ray mutagenesis. Among them, 26 of the new sina mutants are embryonic, larval, or pupal lethal, and stronger than the five published sina mutants ( sina 1 , sina 2 , sina 3 , sina 4 , and sina 5 ) which are early adult lethal. By sequencing the SINA-coding region of sina ES10 , sina ES26 , sina ES79 , and sina ES473 homozygous mutant animals, we identified three invariable amino acid residues in SINA’s RING-domain whose single point mutation ablates SINA function. To demonstrate the functional conservation of this medically important family of RING domain E3 ligases in Drosophila , we established a collection of transgenic lines, expressing either wild type (WT) or proteolysis-deficient (PD) SINA/SIAH inhibitors of Drosophila SINA WT/PD and human SIAH1 WT/PD /2 WT/PD under tissue-specific GAL4-drivers in Drosophila eye, wing, and salary gland. Our results showed that Drosophila SINA and human SIAH1/2 are functionally conserved. Our bioengineered SINA PD /SIAH PD inhibitors are effective in blocking the RAS-dependent neuronal cell fate determination in Drosophila .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":129492,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":581059,"name":"Yajun Cao","orcid":"0000-0002-6392-1195","position":1,"is_corresponding":false},{"id":232396,"name":"Amy Tang","orcid":"0000-0002-5772-2878","position":2,"is_corresponding":false},{"id":581058,"name":"Robert E. Van Sciver","orcid":"0000-0002-1818-2661","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-18T23:15:49.682497Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}