Altered splicing in exon 8 of the DNA replication factor CIZ1 affects subnuclear distribution and is associated with Alzheimer's disease

Abstract

In order to understand the gene-mediated processes underlying sporadic Alzheimer's disease (AD), we carried out a subtractive cloning screen for novel AD candidate genes. We identified the gene encoding the DNA replication factor CIZ1 (CDKN1A interacting zinc finger protein 1) as being more highly expressed in Alzheimer tissue than in healthy brains. We show here that an isoform of CIZ1 which lacks a glutamine-rich region, due to alternative splicing in exon 8, is upregulated in AD brains relative to the full-length CIZ1 protein. We demonstrate for the first time that a minimal 28 amino acid sequence within this region is required for CIZ1 to associate with the nuclear matrix and to form nuclear foci.

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

“…In contrast, contact-inhibited normal fetal lung fibroblast MRC5 cells did not resume proliferation or restore CIZ1 -F expression when boosted with serum (Figure 3(e)). This suggests that stable contact-induced growth arrest suppresses expression of CIZ1 -F. In the same MCF-7 cell populations we observed additional effects on CIZ1 alternative splicing, most notably increased CIZ1 -S (Supplementary Figure 3(a)) an isoform reported to be upregulated in Alzheimer’s disease (Supplementary Table 1), and changes in CIZ1 -Δ4 (Supplementary Figure 3(b)) [2,3]. Together the data show that CIZ1-F mRNA and protein are expressed in proliferating cells and inhibited by both serum-deprivation-induced proliferation arrest (MCF-7), and contact-inhibition-induced proliferation arrest (MRC5).…”

“…We and others have shown that CIZ1 is a NM protein, defined by its resistance to extraction of chromatin [3,8], which suggests that its function is connected to nuclear architecture, possibly contributing to the spatial regulation of nuclear processes [6–8,18,24]. Although the NM appears to be corrupted in certain types of cancer [25] previous work [26–28] and our own experiments indicate that MCF-7 cells retain a NM structure to some extent.…”

“…In fact in MCF-7 cells, they seem to be inversely related to CIZ1 -F, with CIZ1 -S and CIZ1 -Δ4 being more highly expressed in arrested cells (Supplementary Figure 3). It is worth noting that both CIZ1 -F and CIZ1 -S variants are the product of exon 8 splicing events, and that exon 8 splicing patterns have been implicated in Alzheimer’s disease and cervical dystonia [3,14]. …”

“…CIZ1 has also been reported to be involved in the development of breast cancer [12], the most common type of cancer in women [13]. Alternative splicing of CIZ1 is implicated in other chronic diseases including upregulation of a form in which part of exon 8 is excluded (CIZ1-S) in Alzheimer’s disease [3], and in cervical dystonia where mutations in an exonic splicing enhancer may affect splicing patterns [14].

10.1080/15384101.2018.1526600-F0001Figure 1.Human CIZ1 and variant CIZ1-F.(A) Exonic sequence in messenger RNA of full-length and CIZ1 -F, with location of primers (pri) and Taqman probes indicated.

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The impact of microRNAs and alternative splicing in pharmacogenomics

“…Growing evidence is also indicating that defects in the alternative splicing pathways and generation of wrong alternative variants is a common feature of complex diseases. 88 However, the implications of splice variants in gene networks and how they can affect the metabolism of drugs in patients remains to be explored.…”