RB's original CIN?

Abstract

The retinoblastoma tumor suppressor RB is the downstream mediator of a cellular pathway that is thought to prevent cancer by controlling the ability of cells to enter or exit the cell cycle in G0/G1. Recently, however, accumulating evidence has suggested that RB, its family members p107 and p130, and their partners, the E2F family of transcription factors, may have important cellular functions beyond the G1/S transition of the cell cycle, including during DNA replication and at the transition into mitosis. In this issue of Genes & Development, three studies demonstrate a critical role for RB in proper chromosome condensation, centromeric function, and chromosome stability in mammalian cells, and link these cellular functions of RB to tumor suppression in mice. Here we discuss how transcriptional and post-transcriptional mechanisms under the control of the RB pathway ensure accurate progression through mitosis, thereby preventing cancer development.

Figure 1.

Loss of RB function triggers CIN by several mechanisms. Inactivation of RB and its family members, p107 and p130, results in deregulated activation of E2F transcription factors. Targets of E2F include MAD2, a critical regulator of the spindle assembly checkpoint in mitosis, as well as enzymes that modify the structure of the DNA, such as the DNMT1 methyltransferase. In addition, loss of RB function may alter the activity of some of its binding partners involved in the control of chromatin structure, such as SUV4-20H. Similarly, loss of RB affects the function of complexes, such as condensin II complexes, involved in mitotic chromosome assembly. Finally, loss of RB family function may lead to the accumulation of DSBs due to defects during DNA replication, including under stress conditions. Altogether, this defines a complex regulatory network of transcriptional and post-transcriptional elements by which the RB pathway controls chromosomal stability at the G2/M transition of the cell cycle.