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Genes Cancer. 2010 Sep;1(9):917-26. doi: 10.1177/1947601910388937.

The "Mutated in Colorectal Cancer" Protein Is a Novel Target of the UV-Induced DNA Damage Checkpoint.

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  • 1Cancer Research Program, Garvan Institute of Medical Research, Sydney, Australia.

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.

KEYWORDS:

DNA damage response; G2/M checkpoint; colorectal cancer; phosphorylation

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