Homeodomain transcription factor and tumor suppressor Prep1 is required to maintain genomic stability

Abstract

Prep1 is a homeodomain transcription factor that is essential in embryonic development and functions in the adult as a tumor suppressor. We show here that Prep1 is involved in maintaining genomic stability and preventing neoplastic transformation. Hypomorphic homozygous Prep1 i/i fetal liver cells and mouse embryonic fibroblasts (MEFs) exhibit increased basal DNA damage and normal DNA damage response after γ-irradiation compared with WT. Cytogenetic analysis shows the presence of numerous chromosomal aberrations and aneuploidy in very early-passage Prep1 i/i MEFs. In human fibroblasts, acute Prep1 down-regulation by siRNA induces DNA damage response, like in Prep1 i/i MEFs, together with an increase in heterochromatin-associated modifications: rapid increase of histone methylation and decreased transcription of satellite DNA. Ectopic expression of Prep1 rescues DNA damage and heterochromatin methylation. Inhibition of Suv39 activity blocks the chromatin but not the DNA damage phenotype. Finally, Prep1 deficiency facilitates cell immortalization, escape from oncogeneinduced senescence, and H-Ras V12 -dependent transformation. Importantly, the latter can be partially rescued by restoration of Prep1 level. The results show that the tumor suppressor role of Prep1 is associated with the maintenance of genomic stability.

Biochemistry of the tale transcription factors PREP, MEIS, and PBX in vertebrates

“…Importantly, they develop tumors at high frequency that, together with other properties, defines Prep1 as a haplo-insufficient tumor suppressor (Longobardi et al, 2010). Further studies have shown that Prep1 in fact protects cells from DNA damage (Iotti et al, 2011). …”

Pericentric and centromeric transcription: a perfect balance required

“…In contrast, the action of the tumor suppressor Prep1 indicates that complete silencing of satellite expression may be just as detrimental as derepression. Prep1 (also known as PKNOX1 or PBX/knotted 1 homeobox1 in human) is implicated in controlling DNA damage and regulating histone methylation levels (Iotti et al 2011). When Prep1 levels are downregulated in mouse or human cells, DNA damage increases, which leads, through an unknown mechanism, to a widespread increase in the repressive histone mark H3K9me3 (Iotti et al 2011) (Fig.…”

“…A few recent studies have addressed how and why centromeric transcription changes during oncogenesis (Frescas et al 2008;Iotti et al 2011;Slee et al 2012;Ting et al 2011;Zhu et al 2011). The tumor suppressor lysine-specific demethylase 2A (KDM2A) was identified as a heterochromatin associated protein that is downregulated in prostate cancer (Frescas et al 2008).…”

Prep1 and Meis1 competition for Pbx1 binding regulates protein stability and tumorigenesis

“…Moreover, tissue microarray immunohistochemistry revealed that PREP1 is absent or underexpressed in more than 70% of human tumors (17). In fact, in mouse and human cells in culture, Prep1 deficiency leads to genomic instability and accumulation of DNA damage, a condition that favors malignancy (19).…”