Destabilization of CHK2 by a missense mutation associated with Li-Fraumenisyndrome

Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associ ated with germ-line mutations in TP53. In a kindred with LFS without an inh erited TP53 mutation, we have previously reported a truncating mutation (11 00delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here , we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from > 12 0 min to 30 min. This effect is abrogated by treatment of cells with a prot eosome inhibitor, suggesting that CHK2(R145W) is targeted through this degr adation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are as sociated with loss of the wild-type allele in the corresponding tumor speci mens, and neither tumor harbors a somatic TP53 mutation. Our observations s upport the functional significance of CHK2 mutations in rare cases of LFS a nd suggest that such mutations may substitute for inactivation of TP53.