title: Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells.
abstract: CIZ1 is a nuclear-matrix-associated DNA replication factor unique to higher eukaryotes, for which alternatively spliced isoforms have been associated with a range of disorders. In vitro, the CIZ1 N-terminus interacts with cyclin E and cyclin A at distinct sites, enabling functional cooperation with cyclin-A-Cdk2 to promote replication initiation. C-terminal sequences anchor CIZ1 to fixed sites on the nuclear matrix, imposing spatial constraint on cyclin-dependent kinase activity. Here we demonstrate that CIZ1 is predominantly expressed as a predicted full-length product throughout mouse development, consistent with a ubiquitous role in cell and tissue renewal. CIZ1 is expressed in proliferating stem cells of the testis, but is notably downregulated following commitment to differentiation. Significantly, CIZ1 is re-expressed at high levels in non-proliferative spermatocytes before meiotic division. Sequence analysis identifies at least seven alternatively spliced variants, including a dominant cancer-associated form and a set of novel isoforms. Furthermore, we show that in these post-replicative cells, CIZ1 interacts with germ-cell-specific cyclin A1, which has been implicated in the repair of DNA double-strand breaks. Consistent with this role, antibody depletion of CIZ1 reduces the capacity for testis extract to repair digested plasmid DNA in vitro. Together, the data imply post-replicative roles for CIZ1 in germ cell differentiation that might include meiotic recombination - a process intrinsic to genome stability and diversification.
authors.affiliation: Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds, UK.
authors.forename: Erin A
authors.initials: EA
authors.lastname: Greaves
authors.forename: Nikki A
authors.initials: NA
authors.lastname: Copeland
authors.forename: Dawn
authors.initials: D
authors.lastname: Coverley
authors.forename: Justin F X
authors.initials: JF
authors.lastname: Ainscough
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D049109:Cell Proliferation; D056750:Cyclin A1 / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013091:Spermatogenesis; D013093:Spermatogonia / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism
chemical_list: C540084:Ciz1 protein, mouse; D056750:Cyclin A1; D009687:Nuclear Proteins; D020033:Protein Isoforms