Nuclear Functions of TOR: Impact on Transcription and the Epigenome

Abstract

The target of rapamycin (TOR) protein kinase is at the core of growth factor- and nutrient-dependent signaling pathways that are well-known for their regulation of metabolism, growth, and proliferation. However, TOR is also involved in the regulation of gene expression, genomic and epigenomic stability. TOR affects nuclear functions indirectly through its activity in the cytoplasm, but also directly through active nuclear TOR pools. The mechanisms by which TOR regulates its nuclear functions are less well-understood compared with its cytoplasmic activities. TOR is an important pharmacological target for several diseases, including cancer, metabolic and neurological disorders. Thus, studies of the nuclear functions of TOR are important for our understanding of basic biological processes, as well as for clinical implications.

Keywords: TORC1; TORC2; acetylation; cancer; epigenetics; genomic stability; histones; methylation; target of rapamycin; transcription.

Figure 1

Role of the ScTORC1 complex in epigenetic and transcriptional regulation. Known ScTORC1 downstream epigenetic and transcriptional effectors at the rDNA (A), RP genes (B), and metabolic genes (C). Dashed arrows indicate regulation that is either indirect, or not yet known to be direct. Solid lines indicate direct regulation. Those pathways whose mechanisms have been described in detail are illustrated. Details are described in the text.

Figure 2

Role of the mTORC1 complex in transcriptional regulation. Known mTORC1 transcriptional roles at the 5S and tRNA genes (A), mitochondrial genes (B), and nuclear receptor activated metabolic genes (C). Dashed arrows indicate regulation that is either indirect, or not yet known to be direct. Solid lines indicate direct regulation. Details are outlined in the text. Only pathways whose mechanisms have been characterized in depth are represented.

Figure 3

Roles of the mTORC2 complex in transcriptional and epigenetic regulation. Dashed arrows indicate regulation that is either indirect, or not yet known to be direct. Solid lines indicate direct regulation. P denotes phosphorylation. Yellow circles indicate proteins that physically interact with mTORC2. Blue circles indicate proteins that are regulated by mTORC2 or AKT outside of the nucleus. The link between mTORC2 and BRCA1 (grey letters) is more recent and yet to be tested more rigorously.

Figure 4

Role of the SpTORC2 complex in transcriptional and epigenetic regulation. Dashed arrows indicate regulation that is either indirect, or not yet known to be direct. Solid lines indicate direct regulation. P denotes phosphorylation. The P circled with a dashed line indicates uncertainty about in vivo phosphorylation. Yellow circles indicate proteins that physically interact with Gad8. Notably, Paf1, Leo1, Taf12, and Pab1 are found primarily in the nucleus.