Human Molecular Genetics Advance Access originally published online on August 5, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, Review Issue 2 R159-R165
DOI: 10.1093/hmg/ddg259
© 2003 Oxford University Press
Exposing the MYtH about base excision repair and human inherited disease
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK
Received June 19, 2003; Accepted July 29, 2003
 |
ABSTRACT |
|---|
TOP
ABSTRACT
THE BASE EXCISION REPAIR...Base excision repair (BER) protects against damage to DNA from reactive oxygen species, methylation, deamination, hydroxylation and other by-products of cellular metabolism. Until last year, inherited deficiencies in the BER pathway had not been causally linked with any human genetic disorder. An apparent explanation was functional redundancy between proteins in this and other pathways. However, it was recently discovered that biallelic mutations in the BER DNA glycosylase MYH lead to an autosomal recessive syndrome of adenomatous colorectal polyposis and very high colorectal cancer risk. We review the molecular mechanism of tumourigenesis in MYH polyposis, the preliminary delineation of the MYH polyposis phenotype and the functional overlap of MYH with other repair proteins.
|
THE BASE EXCISION REPAIR PATHWAY |
|---|
The base excision repair (BER) pathway plays a significant role in the repair of mutations caused by reactive oxygen species (ROS) that are generated during aerobic metabolism (1). BER is a multi-step process that involves the sequential activity of several proteins. DNA glycosylases initiate this repair pathway by recognizing and removing a damaged or improper base by hydrolysing the N-glycosidic bond. To date, 10 DNA glycosylases have been characterized and cloned in humans, and each excises an overlapping subset of oxidized, deaminated, alkylated or mismatched bases (2). To complete the repair process, the apurinic/apyrimidinic (AP) site is further processed by an incision step, DNA synthesis, an excision step, and DNA ligation through either the short or long-patch BER pathways. Despite the critical nature of these functions, knockout mouse models of individual glycosylases appeared to be phenotypically normal. Partial redundancy between glycosylases and an overlap with transcription coupled repair was proposed as a likely explanation (3). Furthermore, although inherited deficiencies involving components of the nucleotide excision repair, mismatch repair and recombinational repair pathway had all been linked to specific human genetic disorders, no inherited disorder of BER had been identified (3).
|
ESTABLISHED COLORECTAL CANCER GENES |
|---|
Inherited factors are thought to play a major role in at least 15% of colorectal cancers (CRC), but established CRC predisposition genes account for only a minority of these (4). Familial adenomatous polyposis (FAP; MIM 175100) is an autosomal dominant disorder associated with the development of hundreds or thousands of colorectal adenomas, some of which progress to cancer. There are a number of associated extracolonic manifestations which include congenital hypertrophy of the retinal pigment epithelium (CHRPE), upper gastrointestinal tumours, desmoid tumours, hepatoblastoma, epidermoid skin cysts and benign osteoid tumours (Gardner's syndrome) and cerebellar medulloblastoma (Turcot syndrome). FAP is caused by inherited mutations within the adenomatous polyposis coli (APC) gene that acts as a gatekeeper regulating proliferation of colonic cells (5). Tumours develop in patients with FAP after somatic inactivation of the wild-type APC allele in accordance with Knudson's ‘2-hit hypothesis’, and it has recently been suggested that different combinations of APC mutation confer different growth advantages in colorectal tumours (6–8). Attenuated FAP (AFAP) is associated with smaller numbers of adenomas and is caused by germline mutations in the extreme 5' or 3' ends of APC or in the alternatively spliced region of exon 9 (5). Tumour development in at least some cases of AFAP appears to require somatic second and third hits of the wild-type and attenuated APC alleles (9,10).
Hereditary non-polyposis CRC (HNPCC; MIM 114500) is an autosomal dominant disorder characterized by early-onset CRC (in the absence of florid polyposis) and other extra-colonic cancers, notably endometrial cancer and cancers of the stomach, small bowel, ureter and renal pelvis. HNPCC is caused by inherited deficiencies in the mismatch repair (MMR) pathway (11). Germline mutations are most frequently found in MSH2 and MLH1, and cause a high degree of somatic microsatellite instability (MSI) in the associated colorectal tumours. Mutations in MSH6 are less frequent and are associated with less marked MSI. For mismatch recognition, the MSH2 protein forms a heterodimer with MSH6 or MSH3 depending on whether base–base mispairs (MSH2/MSH6) or insertion-deletion loops (MSH2/MSH3 and/or MSH2/MSH6) are repaired (11). Tumour development in HNPCC requires somatic inactivation of the wild-type MMR allele, again in accordance with Knudson's ‘2-hit’ hypothesis (11).
|
ADENOMATOUS COLORECTAL POLYPOSIS AND INHERITED MUTATIONS OF MYH |
|---|
Al-Tassan et al. (12) investigated a British family (family N) in which three siblings were affected by multiple colorectal adenomas and carcinoma. Sequencing of the entire APC open reading frame (ORF) in constitutional DNA samples from two of the affected siblings, together with haplotype and expression analyses, excluded an inherited APC gene defect. Assessment for MSI in DNA extracted from 11 tumours from family N also excluded an underlying MMR defect. However, the pattern of somatic APC mutations in tumours from family N provided a clue as to the underlying genetic defect. Sequencing of the APC ORF in each of the 11 tumours revealed 18 somatic mutations, 15 of which were G:C
T:A transversions (12). This class of mutations accounts for only some 10% of reported somatic APC mutations, with frameshift mutations and loss of heterozygosity being the more usual classes of mutations leading to somatic inactivation of APC in colorectal tumours (8,12). Comparison of the findings in family N with a database of over 800 somatic APC mutations from sporadic and FAP-associated colorectal tumours, confirmed that the excess of G:CT:A transversions in family N was highly significant (P=10-12).
8-Oxo-7,8-dihydro2'deoxyguanosine (8-oxoG) is the most stable product of oxidative DNA damage (13) and readily mispairs with adenines (14), leading to G:CT:A mutations in repair-deficient bacteria and yeast (15–18). In Escherichia coli, three enzymes help protect cells against the mutagenic effects of guanine oxidation (16). MutM DNA glycosylase removes the oxidized base from 8-oxoG:C base pairs in duplex DNA, MutY DNA glycosylase excises adenines misincorporated opposite unrepaired 8-oxoG during replication, and MutT, an 8-oxo-dGTPase, prevents the incorporation of 8-oxo-dGMP into nascent DNA (Fig. 1). Homologues of mutM, mutY and mutT have been identified in human cells and termed OGG1 (19), MYH (20) and MTH1 (21), respectively.
|
To determine whether an inherited defect in the 8-oxoG repair pathway was responsible for the pattern of somatic G:C
T:A mutations in family N, Al-Tassan et al. (12) sequenced the ORFs of OGG1, MYH and MTH1 in a blood DNA sample from an affected sibling. Two non-conservative amino acid variants were identified in MYH (Y165C and G382D), but no likely pathogenic changes were identified in OGG1 or MTH1. All three affected siblings from family N were found to be compound heterozygotes for Y165C and G382D and the unaffected family members were either heterozygous for one of these variants or normal, suggesting transmission as an autosomal recessive trait. Consistent with this, no somatic mutations in MYH were identified upon comprehensive analysis of the 11 MYH-deficient colorectal tumours (12).
In an attempt to identify further cases, Jones et al. (22) sequenced the MYH ORF in 21 unrelated patients with multiple (>10) colorectal adenomas with or without carcinoma, and identified seven patients with biallelic germline MYH mutations, including four cases homozygous for nonsense changes. Six patients had over 100 adenomas and the seventh had 25 adenomas in 22 cm of resected large bowel. The absence of any history of colorectal adenomas or carcinoma in the obligate heterozygote parents and the occurrence of adenomatous polyposis in two siblings of one index case, was consistent with the transmission as an autosomal recessive trait (22). Analysis of somatic APC mutations in colorectal adenomas and carcinomas again revealed a highly significant excess of somatic G:CT:A mutations, confirming the mutational basis of MYH polyposis (22).
|
MYH POLYPOSIS, FAP AND AFAP |
|---|
As many as one-quarter of classical FAP patients (>100 macroscopic adenomas) occur as sporadic cases and others have affected siblings with unaffected parents (23). It has been proposed that such cases result from de novo APC gene mutations or gonadal mosaicism in a clinically unaffected parent. Among cases with three to 100 colorectal adenomas (consistent with AFAP) only a small minority (perhaps 10%) have germline mutations of APC (24). To determine whether a significant proportion of FAP and AFAP-like cases have mutations in MYH, Sampson et al. (25) analysed 111 apparently unrelated families identified from six regional polyposis registers in the UK with no vertical transmission of polyposis, at least 10 colorectal adenomas with or without colorectal cancer in the index case and no known truncating APC mutation (although comprehensive analysis of APC had not been undertaken in all cases). Biallelic germline MYH mutations were identified in 23% (25 cases), a finding that has important implications for accurate genetic counselling, genetic testing and effective planning of surveillance colonoscopy for extended family members.
Sieber et al. (26) recently identified biallelic germline MYH mutations in six of 152 patients with multiple (three to 100) colorectal adenomas. Significantly, around one-third of patients with between 15 and 100 adenomas had biallelic MYH mutations. They also identified biallelic mutation of MYH in 8/107 APC-mutation-negative FAP-like cases (>100 colorectal adenomas).
The mean age at diagnosis of the 25 unrelated MYH polyposis cases reported by Sampson et al. (25) was 46 years (median 48 years, range 13–65 years; Table 1). Nine were specified as having over 100 adenomas (one had over 400), 11 had 10–100 adenomas, and in five, the adenomas were ‘multiple, too many to count’, ‘numerous’ or ‘throughout the colon’. Twelve of the 25 index cases (48%) had colorectal cancer diagnosed at a mean age of 49.7 years. The index cases had a total of 64 siblings of whom 17 (27%) were known to be affected by colorectal polyposis, consistent with autosomal recessive transmission.
|
Among the 14 cases with biallelic MYH mutations identified by Sieber et al. (26), the age at diagnosis ranged from 30 to 70 years, the total number of polyps ranged from 18 to 1000, and 50% had colorectal cancer. Both Sampson et al. (25) and Sieber et al. (26) reported the identification of microadenomas in the background colorectal mucosa in patients with biallelic MYH mutations. Previously, this feature had been considered pathognomonic of FAP (27). Duodenal adenomas have also been noted in several patients (as found in patients with FAP due to germline mutation of APC) and possible CHRPE noted in one. No other frequent phenotypic manifestations of biallelic MYH mutation have been reported to date.
Together, these data indicate that the colorectal phenotype of MYH polyposis may closely resemble AFAP (<100 adenomas), or FAP (100–1000 adenomas), but not severe FAP (>1000 adenomas; Table 1). We propose that this may reflect the number of somatic mutations required for initiation of adenoma development. In FAP, adenoma development requires only a single somatic APC mutation. Families with biallelic MYH mutations may be more comparable to patients with AFAP who develop smaller numbers of adenomas that require two somatic APC mutations for initiation (9,10). By contrast, most patients with HNPCC develop only one or a few adenomas or carcinomas whose initiation requires somatic inactivation of a wild-type MMR allele and two somatic APC mutations in the target cell.
|
SOMATIC G:CT:A MUTATIONS PRIMARILY OCCUR AT GAA SEQUENCES IN APC
|
|---|
Analyses of MYH-deficient colorectal tumours have shown that the two bases immediately 3' to the somatically mutated G are almost always AA and this preponderance of G:C
T:A mutations at GAA sequences is highly significant (12,22). This sequence specificity occurs irrespective of the nature of the germline MYH mutations (including very early truncating mutations which are predicted to result in a complete absence of functional MYH) (22). Recently, Chmiel et al. (28) demonstrated that wild-type MutY has a 3-fold decrease in adenine glycosylase activity on a GAA containing duplex as compared with non-GAA containing duplex. These data indicate that the GAA sequence specificity may not reflect a direct function of MYH but, more likely, improper recognition/repair by compensatory glycosylases.
A possible explanation for the apparently specific predisposition to colonic tumours in patients with MYH defects is the high level of oxidative damage affecting this organ (29). However, the prevalence of GAA target sites in APC as compared with other key genes involved in tumourigenesis may also be a factor. APC has a total of 216 GAA sites in which G:CT:A mutations could lead to termination codons, whereas TP53, PTCH, RB1, NF1 and VHL (that are frequently mutated during tumourigenesis in the brain/breast/lung, skin, retina, Schwann cells and kidney) have only 12, 34, 61, 139 and eight sites, respectively. Although the prevalence of GAA sites in APC and high levels of oxidative damage in the gut may contribute towards the colorectal phenotype seen in association with MYH deficiency, the reasons underlying this phenotype specificity remain unclear.
|
THE SPECTRUM OF MYH MUTATIONS AND DIAGNOSTIC ISSUES |
|---|
To-date, six truncating (252delG, Y90X, Q324X, 1103delC, E466X and 1419delC), four missense (W117R, Y165C, V232F and G382D), one in-frame insertion (137insIW) and two putative splice site mutations (347-1G
A and 891+3AC) have been reported in MYH in patients with colorectal polyposis (12,22,25,26) (Fig. 2). Although there has been some bias in the ascertainment of MYH-deficient cases, by far the most common mutations among Caucasians are Y165C (36 mutations, 53%) and G382D (22 mutations, 32%) (25,26) (Fig. 3). Specific mutations in MYH have been identified in different ethnic populations and diagnostic screening strategies will have to be optimised accordingly. For example, E466X accounts for all (8/8) mutations so far reported in Indian cases (25).
|
|
|
FUNCTIONAL DOMAINS AND BIOCHEMISTRY OF mutY/MYH |
|---|
Although only limited data is available on MYH due to the difficulty of expressing the protein (30–34), Parker et al. (35) have shown that MYH interacts with AP endonuclease, PCNA, and RPA, suggesting a role in long patch BER and Boldogh et al. (36) have shown an association with the replication foci, suggesting a role in replication-coupled repair. More extensive structural and biochemical information is available on MutY. The N-terminal domain of MutY (Met-1 to Lys-225) contains the catalytic region (37) and shares several motifs with other BER glycosylases, including the helix–hairpin–helix (HhH), pseudo HhH and the iron–sulfur cluster loop motif (38). MutY contains a C-terminal domain that is not found in the BER glycosylase superfamily, with sequence and structural homo-logy to MutT (39) and the C-terminal domain of MYH correspondingly shares homology with MTH1 (40). NMR and biochemical studies have suggested that the C-terminal domain plays a role in 8-oxoG recognition (39,41,42).
MutY is a monofunctional BER glycosylase that is capable of removing adenine from 8-oxoG:A, G:A, and C:A mispairs (43). Like all DNA–nucleotide-modifying enzymes, MutY has to recognise and access chemical adducts on DNA bases hidden within the double helix of DNA (44–46). These enzymes expose their targets by rotating the phosphodiester bonds surrounding the nucleotide, causing the target base to be flipped out of the DNA helix (47–52). Crystallographic studies on the catalytic core of MutY have revealed an active site binding pocket for the extruded adenine (38), indicating that MutY uses a base-flipping mechanism, with compression of the DNA intrastrand phosphate distance by the HhH and pseudo-HhH motifs. However, MutY is unique among BER enzymes in recognizing a mismatch between a damaged 8-oxoG and a normal adenine while exclusively catalysing the removal of the undamaged base (42,53,54). On the basis of NMR studies, a double base flipping mechanism for MutY has recently been proposed in which both adenine and 8-oxoG are flipped from the helix during the repair process (55).
|
FUNCTIONAL ANALYSIS OF THE COMMON MISSENSE MUTATIONS Y165C AND G382D |
|---|
Amino acids identical or similar to tyrosine at residue 165 and glycine at residue 382 are present in MYH homologues from bacteria, yeast, plants and mammals, indicating their likely functional significance (12). To provide insight into the functional consequences of the missense mutations, the equivalent MutY mutations (Y82C and G253D) were assessed for the rate of adenine removal from DNA duplexes containing a G:A or 8-oxoG:A mismatch. When compared with wild-type MutY, the mutant proteins exhibited
90-fold (Y82C) and 6-fold (G253D) slower rates of adenine removal from the G:A substrate at 37°C (12). The Y82C mutant was so severely compromised in its catalytic activity for the 8-oxoG:A substrate at 2°C, that minimal conversion of substrate to product was observed, while the G253D mutant exhibited a 5-fold decreased activity. The dramatic effect of Y82C is consistent with structural studies of MutY which locate Y82 within the pseudo-HhH motif and suggest a role in mismatch specificity and flipping of adenine into the base specificity pocket (38). The reduction in activity of G253D was similar to a truncated form of MutY that lacked the C-terminal third of the protein (42). Chmiel et al. (28) have recently shown that Y165C and G382D in MYH have a significantly reduced ability to complement the activity of MutY in MutY-deficient E. coli. |
FUNCTIONAL OVERLAP WITH OTHER REPAIR PATHWAYS |
|---|
Ni et al. (56) demonstrated that Msh2p/Msh6p in Saccharomyces cerevisiae bind to 8-oxoG:A mismatches and repair 8-oxoG lesions. However, because S. cerevisiae does not contain MutY and MutT homologs, it was initially unclear whether MSH2/MSH6 played a similar role in other organisms. This was recently resolved by Mazurek et al. (57), who showed that human MSH2/MSH6 were activated upon recognition of 8-oxoG. Furthermore, Gu et al. (58) demonstrated that MYH interacts with the MSH2/MSH6 heterodimer via MSH6, and MSH2/MSH6 stimulates the DNA binding and glycosylase activities of MYH with an 8-oxoG:A mismatch. Because both MYH and MSH6 interact with PCNA and co-localize to the replication foci, PCNA may act as a co-ordinator of both repair pathways (35,36,58–61). Therefore, MYH-mediated BER may co-operate with MMR in protecting against the mutagenic effects of 8-oxoG. Other repair pathways have also been implicated in the repair of 8-oxoG: the Cockayne syndrome B gene product may be required for general genome repair (62), and BRCA1 and BRCA2 required for transcription coupled repair (63).
|
CONCLUDING REMARKS |
|---|
Although MYH polyposis appears to be transmitted as an autosomal recessive trait, the risk of colorectal adenoma and carcinoma in heterozygotes has not been determined. Neither is it clear whether inherited mutations in other components of the 8-oxoG repair system, or other BER glycosylases, predispose to tumours in humans. Whatever the outcome of investigations to address these questions, the myth that inherited defects of BER lack phenotypic consequences has now been firmly dispelled.
|
ACKNOWLEDGEMENTS |
|---|
We thank Professor Sheila David for helpful comments and Dr Nada Al-Tassan for help with preparing the figures. J.P.C. and J.R.S. are supported by Cancer Research UK, Tenovus, CETIC (W.D.A.), KEF and the Wales Gene Park.
|
FOOTNOTES |
|---|
* To whom correspondence should be addressed. Tel: +44 2920742652; Fax: +44 2920746551; Email: cheadlejp{at}cardiff.ac.uk
|
REFERENCES |
|---|
- Lindahl, T. (1993) Instability and decay of the primary structure of DNA. Nature, 362, 709–715.[CrossRef][Medline]
-
Wood, R.D., Mitchell, M., Sgouros, J. and Lindahl, T. (2001) Human DNA repair genes. Science, 291, 1284–1289.
[Abstract/Free Full Text] - Hoeijmakers, J.H. (2001) Genome maintenance mechanisms for preventing cancer. Nature, 411, 366–374.[CrossRef][Medline]
- Kinzler, K.W. and Vogelstein, B. (1996) Lessons from hereditary colorectal cancer. Cell, 87, 159–170.[CrossRef][Web of Science][Medline]
-
Fearnhead, N.S., Britton, M.P. and Bodmer, W.F. (2001) The ABC of APC. Hum. Mol. Genet., 10, 721–733.
[Abstract/Free Full Text] - Lamlum, H., Ilyas, M., Rowan, A., Clark, S., Johnson, V., Bell, J., Frayling, I., Efstathiou, J., Pack, K., Payne, S. et al. (1999) The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's ‘two-hit’ hypothesis. Nat. Med., 5, 1071–1075.[CrossRef][Web of Science][Medline]
-
Rowan, A.J., Lamlum, H., Ilyas, M., Wheeler, J., Straub, J., Papadopoulou, A., Bicknell, D., Bodmer, W.F. and Tomlinson, I.P. (2000) APC mutations in sporadic colorectal tumors: a mutational ‘hotspot’ and interdependence of the ‘two hits’. Proc. Natl Acad. Sci. USA, 97, 3352–3357.
[Abstract/Free Full Text] -
Cheadle, J.P., Krawczak, M., Thomas, M.W., Hodges, A.K., Al-Tassan, N., Fleming, N. and Sampson, J.R. (2002) Different combinations of biallelic APC mutation confer different growth advantages in colorectal tumours. Cancer Res., 62, 363–366.
[Abstract/Free Full Text] - Spirio, L.N., Samowitz, W., Robertson, J., Robertson, M., Burt, R.W., Leppert, M. and White, R. (1998) Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps. Nat. Genet., 20, 385–388.[CrossRef][Web of Science][Medline]
- Su, L-K., Barnes, C.J., Yao, W., Qi, Y., Lynch, P.M. and Steinbach, G. (2000) Inactivation of germline mutant APC alleles by attenuated somatic mutations: a molecular genetic mechanism for attenuated familial adenomatous polyposis. Am. J. Hum. Genet., 67, 582–590.[CrossRef][Web of Science][Medline]
-
Peltomaki, P. (2001) Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum. Mol. Genet., 10, 735–740.
[Abstract/Free Full Text] -
Al-Tassan, N., Chmiel, N.H., Maynard, J., Fleming, N., Livingston, A.L., Williams, G.T., Hodges, A.K., Davies, D.R., David, S.S., Sampson, J.R. and Cheadle, J.P. (2002) Inherited variants of MYH associated with somatic G:CT:A mutations in colorectal tumors. Nat. Genet., 30, 227–232.[CrossRef][Web of Science][Medline]
- Ames, B.N. and Gold, L.S. (1991) Endogenous mutagens and the causes of aging and cancer. Mutat. Res., 250, 3–16.[Web of Science][Medline]
- Shibutani, S., Takeshita, M. and Grollman, A.P. (1991) Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature, 349, 431–434.[CrossRef][Medline]
-
Nghiem, Y., Cabrera, M., Cupples, C.G. and Miller, J.H. (1988) The mutY gene: A mutator locus in Eschericia coli that generates G:C to T:A transversions. Proc. Natl Acad. Sci. USA, 85, 2709–2713.
[Abstract/Free Full Text] -
Michaels, M.L. and Miller, J.H. (1992) The GO system protects organisms from the mutagenic effect of the spontaneous lesion 8-hydroxyguanine (7,8-dihydro-8-oxoguanine). J. Bacteriol., 174, 6321–6325.
[Free Full Text] - Moriya, M. and Grollman, A.P. (1993) Mutations in the mutY gene of Escherichia coli enhance the frequency of targeted G:C to T:A transversions induced by a single 8-oxoguanine residue in single-stranded DNA. Mol. Gen. Genet., 239, 72–76.[Web of Science][Medline]
- Thomas, D., Scot, A.D., Barbey, R., Padula, M. and Boiteux, S. (1997) Inactivation of OGG1 increases the incidence of G:C to T:A transversions in Saccharomyces cerevisiae: evidence for endogenous oxidative damage to DNA in eukaryotic cells. Mol. Gen. Genet., 254, 171–178.[CrossRef][Web of Science][Medline]
-
Roldan-Arjona, T., Wei, Y.F., Carter, K.C., Klungland, A., Anselmino, C., Wang, R.P., Augustus, M. and Lindahl, T. (1997) Molecular cloning and functional expression of a human cDNA encoding the antimutator enzyme 8-hydroxyguanine–DNA glycosylase. Proc. Natl Acad. Sci. USA, 94, 8016–8020.
[Abstract/Free Full Text] -
Slupska, M.M., Baikalov, C., Luther, W.M., Chiang, J-H., Wei, Y-F. and Miller, J.H. (1996) Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J. Bacteriol., 178, 3885–3892.
[Abstract/Free Full Text] -
Sakumi, K., Furuichi, M., Tsuzuki, T., Kakuma, T., Kawabata, S., Maki, H. and Sekiguchi, M. (1993) Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA-synthesis. J. Biol. Chem., 268, 23524–23530.
[Abstract/Free Full Text] -
Jones, S., Emmerson, P., Maynard, J., Best, J.M., Jordan, S., Williams, G.T., Sampson, J.R. and Cheadle, J.P. (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:CT:A mutations. Hum. Mol. Genet., 11, 2961–2967.
[Abstract/Free Full Text] - Bisgaard, M.L., Fenger, K., Bulow, S., Niebuhr, E. and Mohr, J. (1994) Familial adenomatous polyposis (FAP): frequency, penetrance, and mutation rate. Hum. Mutat., 3, 121–125.[CrossRef][Web of Science][Medline]
-
Lamlum, H., Al-Tassan, N., Jaeger, E., Frayling, I., Sieber, O., Reza, F.B., Eckert, M., Rowan, A., Barclay, E., Atkin, W. et al. (2000) Germline APC variants in patients with multiple colorectal adenomas, with evidence for the particular importance of E1317Q. Hum. Mol. Genet., 9, 2215–2221.
[Abstract/Free Full Text] - Sampson, J.R., Dolwani, S., Jones, S., Eccles, D., Ellis, A., Evans, D.G., Frayling, I., Jordan, S., Maher, E.R., Mak, T. et al. (2003) Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet, 362, 39–41.[CrossRef][Web of Science][Medline]
-
Sieber, O.M., Lipton, L., Crabtree, M., Heinimann, K., Fidalgo, P., Phillips, R.K., Bisgaard, M.L., Orntoft, T.F., Aaltonen, L.A., Hodgson, S.V., Thomas, H.J. and Tomlinson, I.P. (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. New Engl. J. Med., 348, 791–799.
[Abstract/Free Full Text] - Bussey, H.J. (1979) Familial polyposis coli. Pathol. Annu.14, 61–81.
- Chmiel, N.H., Livingston, A.L. and David, S.S. (2003) Insight into the functional consequences of inherited variants of the hMYH adenine glycosylase associated with colorectal cancer: complemetation assays with hMYH variants and pre-steady-state kinetics of the corresponding mutated E.coli enzymes. J. Mol. Biol., 327, 431–443.[CrossRef][Web of Science][Medline]
- Babbs, C.F. (1990) Free radicals and the etiology of colon cancer. Free Radic. Biol. Med., 8, 191–200.[CrossRef][Web of Science][Medline]
-
Slupska, M.M., Luther, W.M., Chiang, J-H., Yang, H. and Miller, J.H. (1999) Functional expression of hMYH, a human homolog of the Escherichia coli MutY protein. J. Bacteriol., 181, 6210–6213.
[Abstract/Free Full Text] -
Gu, Y. and Lu, A-L. (2001) Differential DNA recognition and glycosylase activity of the native human MutY homolog (hMYH) and recombinant hMYH expressed in bacteria. Nucl. Acid Res., 29, 2666–2674.
[Abstract/Free Full Text] -
Ohtsubo, T., Nishioka, K., Imaiso, Y., Iwai, S., Shimokawa, H., Oda, H., Fujiwara, T. and Nakabeppu, Y. (2000) Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucl. Acid Res., 28, 1355–1364.
[Abstract/Free Full Text] -
Takao, M., Zhang, Q-M., Yonei, S. and Yasui, A. (1999) Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylase. Nucl. Acid Res., 27, 3638–3644.
[Abstract/Free Full Text] -
Shinmura, K., Yamaguchi, S., Saitoh, T., Takeuchi- Sasaki, M., Kim, S.-R., Nohmi, T. and Yokota, J. (2000) Adenine excisional repair function of MYH protein on the adenine:8-hydroxyguanine base-pair in double-stranded DNA. Nucl. Acid Res., 28, 4912–4918.
[Abstract/Free Full Text] -
Parker, A., Gu, Y., Mahoney, W., Lee, S-H., Singh, K.K. and Lu, A-L. (2001) Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long-patch DNA base excision repair. J. Biol. Chem., 276, 5547–5555.
[Abstract/Free Full Text] -
Boldogh, I., Milligan, D., Soog Lee, M., Bassett, H., Lloyd, R.S. and McCullough, A.K. (2001) hMYH cell cycle-dependent expression, subcellular localization and association with replication foci: evidence suggesting replication-coupled repair of adenine:8-oxoguanine mispairs. Nucl. Acids Res., 29, 2802–2809.
[Abstract/Free Full Text] - Manuel, R.C. and Lloyd, R.S. (1997) Cloning, overexpression, and biochemical characterization of the catalytic domain of MutY. Biochemistry, 36, 11140–11152.[CrossRef][Medline]
- Guan, Y., Manuel, R.C., Arvai, A.S., Parikh, S.S., Mol, C.D., Miller, J.H., Lloyd, S. and Tainer, J.A. (1998) MutY catalytic core, mutant and bound adenine structures define specificity for DNA repair enzyme superfamily. Nat. Struct. Biol., 5, 1058–1064.[CrossRef][Web of Science][Medline]
- Noll, D.M., Gogos, A., Granek, J.A. and Clarke, N.D. (1999) The C-terminal domain of the adenine–DNA glycosylase MutY confers specificity of 8-oxoguanine–adenine mispairs and may have evolved from MutT, an 8-oxo-dGTPase. Biochemistry, 38, 6374–6379.[CrossRef][Medline]
- Nakabeppu, Y. (2001) Molecular genetics and structural biology of human MutT homolog MTH1. Mutat. Res., 477, 59–70.[Web of Science][Medline]
- Volk, D.E., House, P.G., Thiviyanathan, V., Luxon, B.A., Zhang, S., Lloyd, R.S. and Gorenstein, D.G. (2000) Structural similarities between MutT and the C-terminal domain of MutY. Biochemistry, 39, 7331–7336.[CrossRef][Medline]
-
Chmiel, N.H., Golinelli, M-P., Francis, A.W. and David, S.S. (2001) Efficient recognition of substrates and substrate analogs by the adenine glycosylase MutY requires the C-terminal domain. Nucl. Acids Res., 29, 553–564.
[Abstract/Free Full Text] - David, S.S. and Williams, S.D. (1998) Chemistry of glycosylases and endonucleases involved in base excision repair. Chem. Rev., 98, 1221–1261.[CrossRef][Web of Science][Medline]
- Cheng, X. and Blumenthal, R.M. (1996) Finding a basis for flipping bases. Structure, 4, 639–645.[Medline]
- Roberts, R.J. and Cheng, X. (1998) Base flipping. A. Rev. Biochem., 67, 181–198.[CrossRef][Web of Science][Medline]
- Hornby, D.P. and Ford, G.C. (1998) Protein-mediated base flipping. Curr. Opin. Biotechnol., 9, 354–358.[CrossRef][Web of Science][Medline]
- Lau, A.Y., Scharer, O.D., Samson, L., Verdine, G.L. and Ellenberger, T. (1998) Crystal structure of a human alkylbase-DNA repair enzyme complexed to DNA: mechanisms for nucleotide flipping and base excision. Cell, 95, 249–258.[CrossRef][Web of Science][Medline]
- Morikawa, K. and Shirakawa, M. (2000) Three-dimensional structural views of damaged-DNA recognition: T4 endonuclease V, E. coli Vsr protein, and human nucleotide excision repair factor XPA. Mutat. Res., 460, 257–275.[Web of Science][Medline]
- O'Gara, M., Horton, J.R., Roberts, R.J. and Cheng, X. (1998) Structures of HhaI methyltransferase complexed with substrates containing mismatches at the target base. Nat. Struct. Biol., 5, 872–877.[CrossRef][Web of Science][Medline]
- Parikh, S.S., Mol, C.D., Slupphaug, G., Bharati, S., Krokan, H.E. and Tainer, J.A. (1998) Base excision repair initiation revealed by crystal structures and binding kinetics of human uracil-DNA glycosylase with DNA. EMBO J., 17, 5214–5226.[CrossRef][Web of Science][Medline]
- Hosfield, D.J., Guan, Y., Haas, B.J., Cunningham, R.P. and Tainer, J.A. (1999) Structure of the DNA repair enzyme endonuclease IV and its DNA complex: double-nucleotide flipping at abasic sites and three-metal-ion catalysis. Cell, 98, 397–408.[CrossRef][Web of Science][Medline]
- Slupphaug, G., Mol, C.D., Kavli, B., Arvai, A.S., Krokan, H.E. and Tainer, J.A. (1996) A nucleotide-flipping mechanism from the structure of human uracil-DNA glycosylase bound to DNA. Nature, 384, 87–92.[CrossRef][Medline]
- Lu, A.L. (2000) Repair of A/G and A/8-oxoG mismatches by MutY adenine DNA glycosylase. Meth. Mol. Biol., 152, 3–16.[Medline]
- Porello, S.L., Leyes, A.E. and David, S.S. (1998) Single-turnover and pre-steady-state kinetics of the reaction of the adenine glycosylase MutY with mismatch-containing DNA substrates. Biochemistry, 37, 14756–14764.[CrossRef][Medline]
- House, P.G., Volk, D.E., Thiviyanathan, V., Manuel, R.C., Luxon, B.A., Gorenstein, D.G. and Lloyd, R.S. (2001) Potential double-flipping mechanism by E. coli MutY. Prog. Nucl. Acid Res. Mol. Biol., 68, 349–364.[Web of Science][Medline]
- Ni, T.T., Marsischky, G.T. and Kolodner, R.D. (1999) MSH2 and MSH6 are required for removal of adenine misincorporated opposite 8-oxo-guanine in S. cerevisiae. Mol. Cell, 4, 439–444.[CrossRef][Web of Science][Medline]
-
Mazurek, A., Berardini, M. and Fishel, R. (2002) Activation of human MutS homologs by 8-oxo-guanine DNA damage. J. Biol. Chem., 277, 8260–8266.
[Abstract/Free Full Text] -
Gu, Y., Parker, A., Wilson, T.M., Bai, H., Chang, D.Y. and Lu, A.L. (2002) Human MutY homolog, a DNA glycosylase involved in base excision repair, physically and functionally interacts with mismatch repair proteins human MutS homolog 2/human MutS homolog 6. J. Biol. Chem., 277, 11135–11142.
[Abstract/Free Full Text] -
Clark, A.B., Valle, F., Drotschmann, K., Gary, R.K. and Kunkel, T.A. (2000) Functional interaction of proliferating cell nuclear antigen with MSH2-MSH6 and MSH2-MSH3 complexes. J. Biol. Chem., 275, 36498–36501.
[Abstract/Free Full Text] - Flores-Rozas, H., Clark, D. and Kolodner, R.D. (2000) Proliferating cell nuclear antigen and Msh2p–Msh6p interact to form an active mispair recognition complex. Nat. Genet., 26, 375–378.[CrossRef][Web of Science][Medline]
-
Kleczkowska, H.E., Marra, G., Lettieri, T. and Jiricny, J. (2001) hMSH3 and hMSH6 interact with PCNA and colocalize with it to replication foci. Genes Dev., 15, 724–736.
[Abstract/Free Full Text] -
Tuo, J., Muftuoglu, M., Chen, C., Jaruga, P., Selzer, R.R., Brosh, R.M., Rodriguez, H., Dizdaroglu, M. and Bohr, V.A. (2001) The Cockayne Syndrome group B gene product is involved in general genome base excision repair of 8-hydroxyguanine in DNA. J. Biol. Chem., 276, 45772–45779.
[Abstract/Free Full Text] -
Le Page, F., Randrianarison, V., Marot, D., Cabannes, J., Perricaudet, M., Feunteun, J. and Sarasin, A. (2000) BRCA1 and BRCA2 are necessary for the transcription-coupled repair of the oxidative 8-oxoguanine lesion in human cells. Cancer Res., 60, 5548–5552.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Gorgens, S. Kruger, E. Kuhlisch, C. Pagenstecher, R. Hohl, H. K. Schackert, and A. Muller Microsatellite Stable Colorectal Cancers in Clinically Suspected Hereditary Nonpolyposis Colorectal Cancer Patients without Vertical Transmission of Disease Are Unlikely to Be Caused by Biallelic Germline Mutations in MYH J. Mol. Diagn., May 1, 2006; 8(2): 178 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Frattini, I. Carnevali, S. Signoroni, D. Balestra, M. L. Moiraghi, P. Radice, L. Varesco, V. Gismondi, G. Ballardini, P. Sala, et al. Cyclooxygenase-2 Expression in FAP Patients Carrying Germ Line MYH Mutations Cancer Epidemiol. Biomarkers Prev., August 1, 2005; 14(8): 2049 - 2052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Bai, S.ân Jones, X. Guan, T. M. Wilson, J. R. Sampson, J. P. Cheadle, and A-L. Lu 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 Nucleic Acids Res., January 26, 2005; 33(2): 597 - 604. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||