Abstract
The E3 ubiquitin ligase RNF168 is a ring finger protein that has been previously identified to play an important regulatory role in the repair of double-strand DNA breaks. In the present study, an unbiased forward genetics functional screen in mouse granulocyte/macrophage progenitor cell line FDCP1 has identified E3 ubiquitin ligase RNF168 as a key regulator of cell survival and proliferation. Our data indicate that RNF168 is an important component of the mechanisms controlling cell fate, not only in human and mouse haematopoietic growth factor dependent cells, but also in the human breast epithelial cell line MCF-7. These observations therefore suggest that RNF168 provides a connection to key pathways controlling cell fate, potentially through interaction with PML nuclear bodies and/or epigenetic control of gene expression. Our study is the first to demonstrate a critical role for RNF168 in the mechanisms regulating cell proliferation and survival, in addition to its well-established role in DNA repair.
Highlights
The expression, replication and repair of DNA are pivotal to the physiological functioning of all cells
Analysis of the role of Ring Finger Protein 168 (RNF168) in human breast cancer cells. Since both the cell lines, mouse FDCP1B and human TF-1, are growth factor dependent haematopoietic cell lines, we extended the study to investigate the role of endogenous RNF168 in the proliferation and survival of human breast cell line MCF-7
A forward genetics strategy for the identification of functionally critical components of cell regulatory mechanisms has several important advantages: first, it is entirely independent of established knowledge; and second, it automatically focuses on elements that have controlling roles rather than on secondary phenomena [51-54]
Summary
The expression, replication and repair of DNA are pivotal to the physiological functioning of all cells. Understanding of the molecular mechanisms, control and integration of these processes is far from complete and this area is the subject of a great deal of research. This is justified, by the obvious importance of these processes in cellular physiology, and by the many examples of abnormalities in these processes contributing to oncogenesis (reviewed by Hanahan and Weinberg [1]). These range from DNA strand break mediated activation of p53 inhibiting haematopoietic progenitor cell differentiation [3,4], and the induction of differentiation by specific DDR genes such as GADD45A in haematopoietic stem cells [5], to the involvement of CDK12 in the regulation of DDR and embryonic development [6] as well as damage-induced modulation of miRNAs that affect cell cycle progression, apoptosis and differentiation [7,8,9]
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