Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation.

Proc Natl Acad Sci U S A 2002 Nov 4;99(23):14937-42. Epub 2002 Nov 4.

Department of Cell Biology, Biostatistics Core, Albert Einstein Cancer Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

Mbd4 (methyl-CpG binding domain 4) is a novel mammalian repair enzyme that has been implicated biochemically in the repair of mismatched G-T residues at methylated CpG sites. In addition, the human protein has been shown to interact with the DNA mismatch repair protein MLH1. To clarify the role of Mbd4 in DNA repair in vivo and to examine the impact of Mbd4 inactivation on gastrointestinal (GI) tumorigenesis, we introduced a null mutation into the murine Mbd4 gene by gene targeting. Heterozygous and homozygous Mbd4 mutant mice develop normally and do not show increased cancer susceptibility or reduced survival. Although Mbd4 inactivation did not increase microsatellite instability (MSI) in the mouse genome, it did result in a 2- to 3-fold increase in C-->T transition mutations at CpG sequences in splenocytes and epithelial cells of the small intestinal mucosa. The combination of Mbd4 deficiency with a germ line mutation in the adenomatous polyposis coli (Apc) gene increased the tumor number in the GI tract and accelerated tumor progression. The change in the GI cancer phenotype was associated with an increase in somatic C-->T mutations at CpG sites within the coding region of the wild-type Apc allele. These studies indicate that, although inactivation of Mbd4 does not by itself cause cancer predisposition in mice, it can alter the mutation spectrum in cancer cells and modify the cancer predisposition phenotype.

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.232579299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC137523PMC
November 2002
32 Reads

Publication Analysis

Top Keywords

mbd4 inactivation
12
mbd4
9
transition mutations
8
mutations cpg
8
cpg sites
8
cancer predisposition
8
cancer
5
3-fold increase
4
combination mbd4
4
result 3-fold
4
genome result
4
instability msi
4
msi mouse
4
mouse genome
4
increase c-->t
4
c-->t transition
4
intestinal mucosa
4
epithelial cells
4
cells small
4
splenocytes epithelial
4

References

(Supplied by CrossRef)

Kolodner et al.
Genes & Development 1996

Modrich et al.
Annual review of biochemistry 1996

Friedberg et al.
Nature reviews. Cancer 2001

Lindahl et al.
Mutation Research 2000

Hoeijmakers et al.
Nature; Physical Science (London) 2001

Hendrich et al.
Molecular and Cellular Biology 1998

Hendrich et al.
Nature; Physical Science (London) 1999

Petronzelli et al.
Journal of cellular physiology 2000

Bellacosa et al.
PNAS 1999

Bellacosa et al.
Cell death and differentiation 2001

Riccio et al.
Nature genetics 1999

Similar Publications