The "Mutated in colorectal Cancer" protein is a novel target of the UV-induced DNA damage checkpoint

Laurent Pangon, Nicholas D. Sigglekow, Mark Larance, Sam Al-Sohaily, Dessislava N. Mladenova, Christina I. Selinger, Elizabeth A. Musgrove, Maija R. J. Kohonen-Corish

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)917-926
Number of pages10
JournalGenes and Cancer
Volume1
Issue number9
DOIs
Publication statusPublished - 2010
Externally publishedYes

Keywords

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

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