Repair of damaged DNA is required for the viability of all organisms. Studies in Drosophila melanogaster, driven by the power of genetic screens, pioneered the discovery and characterization of many genes and pathways involved in DNA repair in animals. However, fewer than half of the alleles identified in these screens have been mapped to a specific gene, leaving a potential for new discoveries in this field. Here we show that the previously uncharacterized mutagen sensitive gene mus302 codes for the Drosophila melanogaster ortholog of the E3 ubiquitin ligase RING finger and WD domain protein 3 (RFWD3). In human cells, RFWD3 promotes ubiquitylation of RPA and RAD51 to facilitate repair of collapsed replication forks and double-strand breaks through homologous recombination. Despite the high similarity in sequence to the human ortholog, our evidence fails to support a role for Mus302 in the repair of these types of damage. Last, we observe that the N-terminal third of RFWD3 is only found in mammals, but not in other vertebrates or invertebrates. We propose that the new N-terminal sequence accounts for the acquisition of a new biological function in mammals that explains the functional differences between the human and the fly orthologs, and that Drosophila Mus302 may retain the ancestral function of the protein.
15Repair of damaged DNA is required for the viability of all organisms. Studies in Drosophila 16 melanogaster, driven by the power of genetic screens, pioneered the discovery and 17 characterization of many genes and pathways involved in DNA repair in animals. However, 18 fewer than half of the alleles identified in these screens have been mapped to a specific gene, 19 leaving a potential for new discoveries in this field. Here we show that the previously 20 uncharacterized mutagen sensitive gene mus302 codes for the Drosophila melanogaster 21 ortholog of the E3 ubiquitin ligase RING finger and WD domain protein 3 (RFWD3). In human 22 cells, RFWD3 promotes ubiquitylation of RPA and RAD51 to facilitate repair of collapsed 23 replication forks and double strand breaks through homologous recombination. Despite the high 24 similarity in sequence to the human ortholog, our evidence fails to support a role for Mus302 in 25 the repair of these types of damage. Last, we observe that the N-terminal third of RFWD3 is 26 only present in mammals and absent in the rest of vertebrates and invertebrates. We propose 27 that the additional N-terminal portion accounts for the acquisition of a new biological function in 28 mammals that explains the functional differences between the human and the fly orthologs, and 29 that Drosophila Mus302 may retain the ancestral function of the protein. 30 31 Introduction 32 DNA damage repair consists on a processes that detect and fix changes in the DNA 33 molecules of cells; DNA repair is required for cell and organismal viability. Drosophila 34 melanogaster has been an important model in the discovery of genes involved in DNA damage 35repair (Sekelsky, 2017). In the 1980s and 1990s, dozens of mutants hypersensitive to the DNA 36 alkylating agent methyl methanesulfonate (MMS) were isolated (mutagen-sensitive genes, mus) 37
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.