title: Mammalian Fbh1 is important to restore normal mitotic progression following decatenation stress.
abstract: We have addressed the role of the F-box helicase 1 (Fbh1) protein during genome maintenance in mammalian cells. For this, we generated two mouse embryonic stem cell lines deficient for Fbh1: one with a homozygous deletion of the N-terminal F-box domain (Fbh1(f/f)), and the other with a homozygous disruption (Fbh1(-/-)). Consistent with previous reports of Fbh1-deficiency in vertebrate cells, we found that Fbh1(-/-) cells show a moderate increase in Rad51 localization to DNA damage, but no clear defect in chromosome break repair. In contrast, we found that Fbh1(f/f) cells show a decrease in Rad51 localization to DNA damage and increased cytoplasmic localization of Rad51. However, these Fbh1(f/f) cells show no clear defects in chromosome break repair. Since some Rad51 partners and F-box-associated proteins (Skp1-Cul1) have been implicated in progression through mitosis, we considered whether Fbh1 might play a role in this process. To test this hypothesis, we disrupted mitosis using catalytic topoisomerase II inhibitors (bisdioxopiperazines), which inhibit chromosome decatenation. We found that both Fbh1(f/f) and Fbh1(-/-) cells show hypersensitivity to topoisomerase II catalytic inhibitors, even though the degree of decatenation stress was not affected. Furthermore, following topoisomerase II catalytic inhibition, both Fbh1-deficient cell lines show substantial defects in anaphase separation of chromosomes. These results indicate that Fbh1 is important for restoration of normal mitotic progression following decatenation stress.
authors.affiliation: Department of Cancer Biology, Division of Radiation Biology, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd., Duarte, CA 91010, USA.
authors.forename: Corentin
authors.initials: C
authors.lastname: Laulier
authors.forename: Anita
authors.initials: A
authors.lastname: Cheng
authors.forename: Nick
authors.initials: N
authors.lastname: Huang
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Stark
mesh_terms: D000705:Anaphase / Q000187:drug effects / Q000235:genetics; D000818:Animals; D055162:Biocatalysis; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D019457:Chromosome Breakage / Q000187:drug effects; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D043864:DNA, Catenated / Q000378:metabolism; D054659:Diketopiperazines; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044783:F-Box Proteins; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D021381:Protein Transport; D051135:Rad51 Recombinase / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D059005:Topoisomerase II Inhibitors
chemical_list: D043864:DNA, Catenated; D054659:Diketopiperazines; D044783:F-Box Proteins; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D051135:Rad51 Recombinase; D004265:DNA Helicases; C553250:Fbh1 protein, mouse; D004250:DNA Topoisomerases, Type II
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