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

Greaves, Erin A. and Copeland, Nikki A. and Coverley, Dawn and Ainscough, Justin F. X. (2012) Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells. Journal of Cell Science, 125. pp. 2466-2477.

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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 cyclins E and A via 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 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 down-regulated following commitment to differentiation. Significantly, CIZ1 is re-expressed at high levels in non-proliferative spermatocytes prior to meiotic division. Sequence analysis identifies at least seven alternatively spliced variants at this time, including a dominant cancer-associated form and a set of novel isoforms. Furthermore, we show that in these post-replicative cells CIZ1 interacts with the germ cell specific cyclin, A1, that has been implicated in DNA double-strand break repair. 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 novel post-replicative roles for CIZ1 in germ cell differentiation that may include meiotic recombination, a process intrinsic to genome stability and diversification.

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