Distinct developmental phenotypes result from mutation of Set8/KMT5A1 and histone H4 lysine 20 in Drosophila melanogaster

dc.contributor.authorAaron Crain
dc.contributor.authorStephen M Klusza
dc.contributor.authorRobin L Armstrong
dc.contributor.authorPriscila Santa Rosa
dc.contributor.authorBrenda R S Temple
dc.contributor.authorBrian D Stahl
dc.contributor.authorDaniel J McKay
dc.contributor.authorA Gregory Matera
dc.contributor.authorRobert J Duronio
dc.date.accessioned2024-05-21T13:41:11Z
dc.date.available2024-05-21T13:41:11Z
dc.description.abstractMono-methylation of histone H4 lysine 20 (H4K20me1) is catalyzed by Set8/KMT5A and regulates numerous aspects of genome organization and function. Loss-of-function mutations in<br>Drosophila melanogaster Set8 or mammalian KMT5A prevent H4K20me1 and disrupt development. Set8/KMT5A also has non-histone substrates, making it difficult to determine<br>which developmental functions of Set8/KMT5A are attributable to H4K20me1 and which to other substrates or to non-catalytic roles. Here, we show that human KMT5A can functionally substitute for Set8 during Drosophila development and that the catalytic SET domains of the two enzymes are fully interchangeable. We also uncovered a role in eye development for the N-terminal domain of Set8 that cannot be complemented by human KMT5A. Whereas Set8 null mutants are inviable, we found that an R634G mutation in the SET domain predicted to ablate catalytic activity resulted in viable adults, suggesting important non-catalytic functions of Set8. Similarly, flies that were engineered to express only unmodifiable H4 histones (H4K20A) can also complete development, but they are phenotypically distinct from H4K20R, Set8null, and Set8 R634G animals. Taken together, our results demonstrate functional conservation of KMT5A and Set8<br>enzymes, as well as distinct roles for Set8 and H4K20me1 in Drosophila development. (121_Klusza)
dc.identifierhttps://doi.org/10.1093/genetics/iyac054
dc.identifier.urihttps://hdl.handle.net/20.500.12951/988
dc.titleDistinct developmental phenotypes result from mutation of Set8/KMT5A1 and histone H4 lysine 20 in Drosophila melanogaster
dc.typeJournal Article, Professional Journal
dcterms.bibliographicCitationBioarxiv (preprint)/Genetics (Published) 221(2), 17, (April 11, 2022)
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