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Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - Cancer-associated variant expression and interaction of CIZ1 with cyclin A1 in differentiating male germ cells
AU - Greaves, Erin A.
AU - Copeland, Nikki A.
AU - Coverley, Dawn
AU - Ainscough, Justin F. X.
PY - 2012/5/15
Y1 - 2012/5/15
N2 - 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.
AB - 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.
KW - Alternative splicing
KW - Cancer
KW - CIZ1
KW - Cyclin A1
KW - Development
KW - Male germ cell
U2 - 10.1242/jcs.101097
DO - 10.1242/jcs.101097
M3 - Journal article
C2 - 22366453
VL - 125
SP - 2466
EP - 2477
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 1477-9137
ER -