Published online 26 January 2005
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Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis
1 Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, MD, USA 2 Institute of Medical Genetics, Cardiff University Heath Park, Cardiff, CF14 4XN, UK 3 Department of Radiation Oncology, University of Maryland Baltimore, MD 21201, USA 4 The University of Maryland Greenebaum Cancer Center Baltimore, MD, USA
*To whom correspondence should be addressed. Tel: +1 410 706 4356; Fax: +1 410 706 1787; Email: aluchang{at}umaryland.edu
Received January 5, 2005. Accepted January 6, 2005.
The base excision repair DNA glycosylase MutY homolog (MYH) is responsible for removing adenines misincorporated into DNA opposite guanine or 7,8-dihydro-8-oxo-guanine (8-oxoG), thereby preventing G:C to T:A mutations. Biallelic germline mutations in the human MYH gene predispose individuals to multiple colorectal adenomas and carcinoma. We have recently demonstrated that hMYH interacts with the mismatch repair protein hMSH6, and that the hMSH2/hMSH6 (hMutS
) heterodimer stimulates hMYH activity. Here, we characterize the functional effect of two missense mutations (R227W and V232F) associated with hMYH polyposis that lie within, or adjacent to, the putative hMSH6 binding domain. Neither missense mutation affects the physical interaction between hMYH and hMSH6. However, hMYH(R227W) has a severe defect in A/8-oxoG binding and glycosylase activities, while hMYH(V232F) has reduced A/8-oxoG binding and glycosylase activities. The glycosylase activity of the V232F mutant can be partially stimulated by hMutS but cannot be restored to the wild-type level. Both mutants also fail to complement mutY-deficiency in Escherichia coli. These data define the pathogenic mechanisms underlying two further hMYH polyposis-associated mutations.
Correspondence may also be addressed to Jeremy P. Cheadle. Tel: +44 2920742652; Fax: +44 2920746551; Email: cheadlejp{at}cardiff.ac.uk
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