Functional Expression of hMYH, a Human Homolog of the
            <i>Escherichia coli</i>
            MutY Protein

Slupska, Malgorzata M.; Luther, Wendy M.; Chiang, Ju‐Huei; Yang, Hanjing; Miller, Jeffrey H

doi:10.1128/jb.181.19.6210-6213.1999

Cited by 161 publications

(49 citation statements)

References 22 publications

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“…In mammals, MutT homolog-1 (MTH1) hydrolyzes oxidized purine nucleoside triphosphates to the monophosphate forms . 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA (Boiteux and Radicella, 2000;Nakabeppu et al, 2006), whereas MutY homolog (MUTYH) removes adenine misincorporated opposite 8-oxoG in template DNA (Slupska et al, 1999;Nakabeppu et al, 2006). These three enzymes play major roles in suppressing spontaneous mutagenesis initiated by oxidation of nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Oka

Ohno

Tsuchimoto

et al. 2008

EMBO J

199

205

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Oxidative base lesions, such as 8-oxoguanine (8-oxoG), accumulate in nuclear and mitochondrial DNAs under oxidative stress, resulting in cell death. However, it is not known which form of DNA is involved, whether nuclear or mitochondrial, nor is it known how the death order is executed. We established cells which selectively accumulate 8-oxoG in either type of DNA by expression of a nuclear or mitochondrial form of human 8-oxoG DNA glycosylase in OGG1-null mouse cells. The accumulation of 8-oxoG in nuclear DNA caused poly-ADP-ribose polymerase (PARP)-dependent nuclear translocation of apoptosis-inducing factor, whereas that in mitochondrial DNA caused mitochondrial dysfunction and Ca 2 þ release, thereby activating calpain. Both cell deaths were triggered by single-strand breaks (SSBs) that had accumulated in the respective DNAs, and were suppressed by knockdown of adenine DNA glycosylase encoded by MutY homolog, thus indicating that excision of adenine opposite 8-oxoG lead to the accumulation of SSBs in each type of DNA. SSBs in nuclear DNA activated PARP, whereas those in mitochondrial DNA caused their depletion, thereby initiating the two distinct pathways of cell death.

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Section: Introductionmentioning

confidence: 99%

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Oka

Ohno

Tsuchimoto

et al. 2008

EMBO J

199

205

View full text Add to dashboard Cite

show abstract

“…The critical steps in DNA repairing by BER in man are carried out by a set of genes, the human orthologues of MutT, MutM and MutY in bacteria (Tajiri et al, 1995), that act synergistically to prevent mutagenesis induced by 8-oxoG. These are, the nucleoside triphosphatase hMTH1, which hydrolyses 8-oxoG-dGTP, limiting the incorporation of 8-oxo-G in DNA from the nucleotide pool (Sakumi et al, 1993) and the DNA glycosylases hOGG1 and hMYH (the human MutY homolog), which excise 8-oxoG:cytosine (Arai et al, 1997;Boiteux and Radicella, 2000) and 8-oxoG:adenine (A) mismatches respectively, in nascent DNA (Slupska et al, 1999;Shinmura et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas

et al. 2004

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“…8‐OxoG DNA glycosylase, encoded by OGG1 , excises 8‐oxoG paired with cytosine in DNA, ( 6 ) while adenine DNA glycosylase encoded by mutY homolog ( MUTYH ) removes adenine from DNA inserted opposite template 8‐oxoG. ( 7,8 )…”

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confidence: 99%

DNA glycosylase encoded by MUTYH functions as a molecular switch for programmed cell death under oxidative stress to suppress tumorigenesis

Oka

Nakabeppu

2011

Cancer Science

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8‐oxoguanine is a major base lesion in DNA or in nucleotides caused by oxidative stress, and is highly mutagenic because it can pair with adenine as well as cytosine. Adenine DNA glycosylase, encoded by the human mutY homolog gene, MUTYH, excises adenine in the nascent strand when inserted opposite 8‐oxoguanine in template DNA, and thus suppresses mutagenesis caused by 8‐oxoguanine that has accumulated in DNA due to oxidative stress. Several germ‐line mutations in MUTYH are predisposed to MUTYH‐associated polyposis, an autosomal recessive disorder characterized by multiple colorectal adenomas and carcinomas. Loss of function of MUTYH leads to an accumulation of somatic mutations in APC and KRAS genes, resulting in the development of adenomas/carcinomas. We recently demonstrated that accumulation of 8‐oxoguanine in nuclear and mitochondrial DNA triggers two distinct cell death pathways that are independent of each other. Both pathways are initiated by the accumulation of MUTYH‐generated single‐strand breaks (SSBs) in nuclear or mitochondrial DNA. Our findings indicate that MUTYH‐induced cell death due to oxidative stress results in an efficient elimination of mutagenic cells that have accumulated high levels of 8‐oxoguanine in their DNAs. It is most likely that loss of function of MUTYH in stem or progenitor cells in the intestinal epithelium of MUTYH‐associated polyposis patients results in escape from programmed cell death; however, accumulated 8‐oxoguanine causes various mutations in APC or KRAS genes in these proliferative cells, thereby promoting tumorigenesis. We thus propose that MUTYH suppresses tumorigenesis under conditions of oxidative stress by inducing cell death and by suppressing mutagenesis. (Cancer Sci 2011; 102: 677–682)

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Functional Expression of hMYH, a Human Homolog of the Escherichia coli MutY Protein

Cited by 161 publications

References 22 publications

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Two distinct pathways of cell death triggered by oxidative damage to nuclear and mitochondrial DNAs

Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas

DNA glycosylase encoded by MUTYH functions as a molecular switch for programmed cell death under oxidative stress to suppress tumorigenesis

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