Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells

Erin A Greaves, Nikki A Copeland, Dawn Coverley, Justin F X Ainscough

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2466-77
Number of pages12
JournalJournal of Cell Science
Volume125
Issue numberPt 10
DOIs
Publication statusPublished - 15 May 2012

Keywords

  • Alternative Splicing
  • Animals
  • Cell Proliferation
  • Cyclin A1
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Neoplastic
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms
  • Nuclear Proteins
  • Protein Binding
  • Protein Isoforms
  • Protein Structure, Tertiary
  • Spermatogenesis
  • Spermatogonia

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