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

Regulation 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. [Display omitted] •The KRAB-domain zinc finger protein Roma/Zfp157 regulates proliferation•Roma regulates expression of the cell-cycle regulators p21Cip1 and geminin•Roma regulates replication fork dynamics and genomic stability•Ablation of Roma in mouse embryonic fibroblasts leads to endoreduplication Ho et al. demonstrate that the transcriptional regulator Roma, a member of the KRAB/Zinc finger protein family, controls cell-cycle progression and replication fork velocity. Loss of Roma in lactating mammary gland results in replication stress and activation of DNA damage signaling pathways.