Mutations in tyrosyl-DNA phosphodiesterase 2 suppress top-2 induced chromosome segregation defects during Caenorhabditis elegans spermatogenesis

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Author(s)Kwah, Ji Kent
Author(s)Bhandari, Nirajan
Author(s)Rourke, Christine
Author(s)Gassaway, Gabriella
Author(s)Jaramillo-Lambert, Aimee
Date Accessioned2024-08-07T19:25:20Z
Date Available2024-08-07T19:25:20Z
Publication Date2024-06-28
DescriptionThis article was originally published in Journal of Biological Chemistry. The version of record is available at: https://doi.org/10.1016/j.jbc.2024.107446. © 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
AbstractMeiosis reduces ploidy through two rounds of chromosome segregation preceded by one round of DNA replication. In meiosis I, homologous chromosomes segregate, while in meiosis II, sister chromatids separate from each other. Topoisomerase II (Topo II) is a conserved enzyme that alters DNA structure by introducing transient double-strand breaks. During mitosis, Topo II relieves topological stress associated with unwinding DNA during replication, recombination, and sister chromatid segregation. Topo II also plays a role in maintaining mitotic chromosome structure. However, the role and regulation of Topo II during meiosis is not well-defined. Previously, we found an allele of Topo II, top-2(it7), disrupts homologous chromosome segregation during meiosis I of Caenorhabditis elegans spermatogenesis. In a genetic screen, we identified different point mutations in 5′-tyrosyl-DNA phosphodiesterase two (Tdp2, C. elegans tdpt-1) that suppress top-2(it7) embryonic lethality. Tdp2 removes trapped Top-2-DNA complexes. The tdpt-1 suppressing mutations rescue embryonic lethality, ameliorate chromosome segregation defects, and restore TOP-2 protein levels of top-2(it7). Here, we show that both TOP-2 and TDPT-1 are expressed in germ line nuclei but occupy different compartments until late meiotic prophase. We also demonstrate that tdpt-1 suppression is due to loss of function of the protein and that the tdpt-1 mutations do not have a phenotype independent of top-2(it7) in meiosis. Lastly, we found that the tdpt-1 suppressing mutations either impair the phosphodiesterase activity, affect the stability of TDPT-1, or disrupt protein interactions. This suggests that the WT TDPT-1 protein is inhibiting chromosome biological functions of an impaired TOP-2 during meiosis.
SponsorMicroscopy access was supported by grants from the NIH-NIGMS (P20 GM103446), the NSF (IIA-1301765) and the State of Delaware. The LSM880 confocal microscope was acquired with a shared instrumentation grant S10 OD016361. The Andor Dragonfly confocal microscope was acquired with a shared instrumentation grant (S10 OD030321) and access was supported by the NIH-NIGMS (P20 GM103446), the NIGMS (P20 GM139760) and the State of Delaware. Some strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 0D010440). This work was supported by a University of Delaware Research Foundation Award and a National Institutes of Health R35GM142524 (A. J.-L.). C. R. was supported by a NIH Predoctoral Fellowship (F31HD106761). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
CitationKwah, Ji Kent, Nirajan Bhandari, Christine Rourke, Gabriella Gassaway, and Aimee Jaramillo-Lambert. “Mutations in Tyrosyl-DNA Phosphodiesterase 2 Suppress Top-2 Induced Chromosome Segregation Defects during Caenorhabditis Elegans Spermatogenesis.” Journal of Biological Chemistry 300, no. 7 (July 2024): 107446. https://doi.org/10.1016/j.jbc.2024.107446.
ISSN1083-351X
URLhttps://udspace.udel.edu/handle/19716/34655
Languageen_US
PublisherJournal of Biological Chemistry
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
Keywordstopoisomerase II
KeywordsTOP-2
Keywordstdp2
KeywordsTDPT-1
Keywordschromosome structure
KeywordsC. elegans
Keywordsmeiosis
TitleMutations in tyrosyl-DNA phosphodiesterase 2 suppress top-2 induced chromosome segregation defects during Caenorhabditis elegans spermatogenesis
TypeArticle
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