The 'Mutated in Colorectal Cancer' protein is a novel target of the UV-induced DNA damage checkpoint.
MCC is a potential tumor suppressor gene, which is silenced by promoter hypermethylation in a subset of colorectal cancers. However, its functions have remained poorly understood. In the present study, we describe a novel function of MCC in the DNA damage response. Several novel phosphorylation sites were identified by mass spectrometry, including 2 highly conserved ATM/ATR consensus sites at serine 118 and serine 120. In addition, exposure to ultraviolet radiation (UV), but not phleomycin, caused PI3K-dependent phosphorylation of MCC and its nuclear localization. Re-expression of MCC in HCT15 colorectal cancer cells led to a G2/M arrest, and MCC knockdown impaired the induction of a G2/M arrest following UV radiation. Finally, mutation of S118/120 to alanine did not affect MCC nuclear shuttling following UV but did impair MCC G2/M checkpoint activity. Thus, these results suggest that MCC is a novel target of the DNA damage checkpoint and that MCC is required for the complete cell cycle arrest in the G2/M phase in response to UV.
|Authors||Pangon, L.; Sigglekow, N.D.; Larance, M.; Al-Sohaily, S.; Mladenova, D.N.; Selinger, C.I.; Musgrove, E.A.; Kohonen-Corish, M.|
|Publisher Name||Genes & Cancer|
|Published Date||2010-06-01 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?10755_11473/10 Pangon Genes Cancer.pdf|