The KRAB Zinc Finger Protein Roma/Zfp157 Is a Critical Regulator of Cell-Cycle Progression and Genomic Stability.

Teresa L.F. Ho,Julian E. Sale,J. Julian Blow,Christine J. Watson,Guillaume Guilbaud

doi:10.1016/j.celrep.2016.03.078

Teresa L.F. Ho, Julian E. Sale + Show 3 more

Open Access

https://doi.org/10.1016/j.celrep.2016.03.078

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Abstract

SummaryRegulation of DNA replication and cell division is essential for tissue growth and maintenance of genomic integrity and is particularly important in tissues that undergo continuous regeneration such as mammary glands. We have previously shown that disruption of the KRAB-domain zinc finger protein Roma/Zfp157 results in hyperproliferation of mammary epithelial cells (MECs) during pregnancy. Here, we delineate the mechanism by which Roma engenders this phenotype. Ablation of Roma in MECs leads to unscheduled proliferation, replication stress, DNA damage, and genomic instability. Furthermore, mouse embryonic fibroblasts (MEFs) depleted for Roma exhibit downregulation of p21Cip1 and geminin and have accelerated replication fork velocities, which is accompanied by a high rate of mitotic errors and polyploidy. In contrast, overexpression of Roma in MECs halts cell-cycle progression, whereas siRNA-mediated p21Cip1 knockdown ameliorates, in part, this phenotype. Thus, Roma is an essential regulator of the cell cycle and is required to maintain genomic stability.

Highlights

The adult mammary gland undergoes cycles of proliferation, differentiation, and regression with every pregnancy
The increase in proliferation in RomaÀ/À glands at 5dG was further supported by an increased proportion of 5-ethynyl-20deoxyuridine (EdU) positive mammary epithelial cells (MECs) (Figures 1A and S1A)
At 10 days lactation (10dL) when cells are terminally differentiated (Faraldo et al, 2002) and non-proliferative in control glands (Figures 1A and S1A), proliferation is still evident in RomaÀ/À glands, suggesting that Roma is required for the transition from cell-cycle progression to quiescence

Summary

Introduction

The adult mammary gland undergoes cycles of proliferation, differentiation, and regression with every pregnancy. Mammary epithelial progenitor cells initially undergo rapid proliferation during pregnancy before differentiation into specialized milk-producing alveolar cells during lactation. We have shown previously that proliferation of alveolar cells during pregnancy is reduced when the transcription factor Stat is ablated (Khaled et al, 2007). KRAB-Zfps constitute the largest family of transcriptional regulators, are found only in tetrapods, and are generally transcriptional repressors (Urrutia, 2003). Various functions for these DNA binding proteins are just beginning to be elucidated (Lupo et al, 2013)

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