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PDBsum entry 5fa5
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Transferase/protein binding
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PDB id
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5fa5
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References listed in PDB file
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Key reference
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Title
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Disordered methionine metabolism in mtap/cdkn2a-Deleted cancers leads to dependence on prmt5.
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Authors
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K.J.Mavrakis,
E.R.Mcdonald,
M.R.Schlabach,
E.Billy,
G.R.Hoffman,
A.Deweck,
D.A.Ruddy,
K.Venkatesan,
J.Yu,
G.Mcallister,
M.Stump,
R.Debeaumont,
S.Ho,
Y.Yue,
Y.Liu,
Y.Yan-Neale,
G.Yang,
F.Lin,
H.Yin,
H.Gao,
D.R.Kipp,
S.Zhao,
J.T.Mcnamara,
E.R.Sprague,
B.Zheng,
Y.Lin,
Y.S.Cho,
J.Gu,
K.Crawford,
D.Ciccone,
A.C.Vitari,
A.Lai,
V.Capka,
K.Hurov,
J.A.Porter,
J.Tallarico,
C.Mickanin,
E.Lees,
R.Pagliarini,
N.Keen,
T.Schmelzle,
F.Hofmann,
F.Stegmeier,
W.R.Sellers.
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Ref.
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Science, 2016,
351,
1208-1213.
[DOI no: ]
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PubMed id
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Abstract
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5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine
salvage pathway. The MTAP gene is frequently deleted in human cancers because of
its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating
data from a large-scale short hairpin RNA-mediated screen across 390 cancer cell
line models, we found that the viability of MTAP-deficient cancer cells is
impaired by depletion of the protein arginine methyltransferase PRMT5.
MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we
found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in
MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely,
reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence.
Thus, MTA accumulation in MTAP-deleted cancers creates a hypomorphic PRMT5 state
that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of
PRMT5 that leverage this dysregulated metabolic state merit further
investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.
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