title: The "Mutated in Colorectal Cancer" Protein Is a Novel Target of the UV-Induced DNA Damage Checkpoint.
abstract: 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.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pangon
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Sigglekow
authors.forename: Mark
authors.initials: M
authors.lastname: Larance
authors.forename: Sam
authors.initials: S
authors.lastname: Al-Sohaily
authors.forename: Dessislava N
authors.initials: DN
authors.lastname: Mladenova
authors.forename: Christina I
authors.initials: CI
authors.lastname: Selinger
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: Maija R J
authors.initials: MR
authors.lastname: Kohonen-Corish