Abstract
Arginine methylation is an essential post-translational modification (PTM) deposited by protein arginine methyltransferases (PRMTs) and recognized by Tudor domain-containing proteins. Of the nine mammalian PRMTs, PRMT5 is the primary enzyme responsible for the deposition of symmetric arginine methylation marks in cells. The staphylococcal nuclease and Tudor domain-containing 1 (SND1) effector protein is a key reader of the marks deposited by PRMT5. Both PRMT5 and SND1 are broadly expressed and their deregulation is reported to be associated with a range of disease phenotypes, including cancer. Hepatocellular carcinoma (HCC) is an example of a cancer type that often displays elevated PRMT5 and SND1 levels, and there is evidence that hyperactivation of this axis is oncogenic. Importantly, this pathway can be tempered with small-molecule inhibitors that target PRMT5, offering a therapeutic node for cancer, such as HCC, that display high PRMT5–SND1 axis activity. Here we summarize the known activities of this writer–reader pair, with a focus on their biological roles in HCC. This will help establish a foundation for treating HCC with PRMT5 inhibitors and also identify potential biomarkers that could predict sensitivity to this type of therapy.
Highlights
Signal transduction is the process by which information is relayed through a cell
PRMT5 is a key regulator of RNA splicing [55], and as an effector molecule for symmetric dimethylarginine (SDMA) marks deposited by PRMT5, it is not surprising that staphylococcal nuclease and Tudor domaincontaining 1 (SND1) is integral to the maintenance of normal splicing programs that can go awry in a cancer setting
While the role that PRMT5 plays in the development of Hepatocellular carcinoma (HCC) is largely circumstantial— elevated PRMT5 levels clearly correlate with the promotion of HCC and poor prognosis of these cancer patients—its effector molecule, SND1, is more solidly implicated as a driver of HCC
Summary
Extracellular signals, such as growth factors or contact points with other cells, stimulate receptors on the cell surface to initiate this process by converting one stimulus (ligand binding) into another (phosphorylation) This signal initiation event is propelled through the cytoplasm and into the nucleus using a series of sequential PTM events that rely on “reader” proteins, or effector molecules, to dock onto a specific PTM and promote the deposition of a new PTM downstream, which in turn is read and relayed by another effector. PRMT5 has emerged as an important player in HCC [12], the fourth leading cause of cancer mortality in the world [13] This link to HCC is strengthened by the fact that a downstream reader of the PRMT5-deposited SDMA marks—SND1—has been identified aasdaowdrnivsterreaomf HreCaCdefor romf tahtieoPnR[M14T],5t-hdoeupgohsittehde SpDreMciAsemmaorlkesc—ulSaNr mD1ec—hhanasisbmeeonf iadcetinotnifireedmasaainds rpivoeorrloyfuHnCdeCrsftooromda. A fifth truncated SN-like domain is split by the Tudor
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