TY - JOUR
T1 - CIZ1-F, an alternatively spliced variant of the DNA replication protein CIZ1 with distinct expression and localisation, is overrepresented in early stage common solid tumours
AU - Swarts, Dorian Rein Andreas
AU - Stewart, Emma Rachael
AU - Higgins, Gillian Sarah
AU - Coverley, Dawn Alison
N1 - © 2018 The Author(s). Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details
PY - 2018/10/6
Y1 - 2018/10/6
N2 - CIZ1 promotes cyclin-dependent DNA replication and resides in sub-nuclear foci that are part of the protein nuclear matrix (NM), and in RNA assemblies that are enriched at the inactive X chromosome (Xi) in female cells. It is subjected to alternative splicing, with specific variants implicated in adult and paediatric cancers. CIZ1-F is characterized by a frame shift that results from splicing exons 8-12 leading to inclusion of a short alternative reading frame (ARF), excluding the previously characterized C-terminal NM anchor domain. Here, we apply a set of novel variant-selective molecular tools targeted to the ARF to profile the expression of CIZ1-F at both transcript and protein levels, with focus on its relationship with the RNA-dependent and -independent fractions of the NM. Unlike full-length CIZ1, CIZ1-F does not accumulate at Xi, though like full-length CIZ1 it does resist extraction with DNase. Notably, CIZ1-F is sensitive to RNase identifying it as part of the RNA-fraction of the NM. In quiescent cells CIZ1-F transcript expression is suppressed and CIZ1-F protein is excluded from the nucleus, with re-expression not observed until the second cell cycle after exit from quiescence. Importantly, CIZ1-F is over-expressed in common solid tumours including colon and breast, pronounced in early stage but not highly-proliferative late stage tumours. Moreover, expression was significantly higher in hormone receptor negative breast tumours than receptor positive tumours. Together these data show that CIZ1-F is expressed in proliferating cells in an unusual cell cycle-dependent manner, and suggest that it may have potential as a tumour biomarker.
AB - CIZ1 promotes cyclin-dependent DNA replication and resides in sub-nuclear foci that are part of the protein nuclear matrix (NM), and in RNA assemblies that are enriched at the inactive X chromosome (Xi) in female cells. It is subjected to alternative splicing, with specific variants implicated in adult and paediatric cancers. CIZ1-F is characterized by a frame shift that results from splicing exons 8-12 leading to inclusion of a short alternative reading frame (ARF), excluding the previously characterized C-terminal NM anchor domain. Here, we apply a set of novel variant-selective molecular tools targeted to the ARF to profile the expression of CIZ1-F at both transcript and protein levels, with focus on its relationship with the RNA-dependent and -independent fractions of the NM. Unlike full-length CIZ1, CIZ1-F does not accumulate at Xi, though like full-length CIZ1 it does resist extraction with DNase. Notably, CIZ1-F is sensitive to RNase identifying it as part of the RNA-fraction of the NM. In quiescent cells CIZ1-F transcript expression is suppressed and CIZ1-F protein is excluded from the nucleus, with re-expression not observed until the second cell cycle after exit from quiescence. Importantly, CIZ1-F is over-expressed in common solid tumours including colon and breast, pronounced in early stage but not highly-proliferative late stage tumours. Moreover, expression was significantly higher in hormone receptor negative breast tumours than receptor positive tumours. Together these data show that CIZ1-F is expressed in proliferating cells in an unusual cell cycle-dependent manner, and suggest that it may have potential as a tumour biomarker.
U2 - 10.1080/15384101.2018.1526600
DO - 10.1080/15384101.2018.1526600
M3 - Article
JO - Cell cycle
JF - Cell cycle
SN - 1538-4101
ER -