The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1+

Jansson, Kristina; Warringer, Jonas; Farewell, Anne; Park, Han-Oh; Hoe, Kwang Lae; Kim, Donguk; Hayles, Jacqueline; Sunnerhagen, Per

doi:10.1016/j.mrfmmm.2008.07.001

Cited by 8 publications

(10 citation statements)

References 36 publications

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“…The 9‐1‐1 complex has previously been reported to stimulate the DNA repair activity of BER [Toueille et al, ; Friedrich‐Heineken et al, ], increasing the recruitment of BER enzymes to DNA damage sites [Helt et al, ]. In the current work, we confirm a strong genetic interaction between myh1 + and the checkpoint sensor gene rad1 + [Jansson et al, ] in that deletion of components causes hypersensitivity to both platinum compounds as well as to DNA DSB inducing agents. We and others have previously shown that the individual components of the 9‐1‐1 complex have different propensities to interact genetically and physically with Myh1 after different treatments such as H 2 O 2 , UV radiation, MMS, and HU [Chang and Lu, ; Jansson et al, ].…”

Section: Discussionsupporting

confidence: 85%

“…We previously described a role of Myh1 in repair of UV radiation-induced DNA damage [Jansson et al, 2008]. In light of the previously found specific genetic interaction between the myh1 and rad1 mutations for UV sensitivity [Jansson et al, 2008], we here analyzed how combined deficiencies in myh1 1 and in either of the 9-1-1 sensor components influenced sensitivity to chemotherapeutic agents causing crosslinks and/or breaks in DNA, respectively.…”

Section: Resultsmentioning

confidence: 99%

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A role for Myh1 in DNA repair after treatment with strand‐breaking and crosslinking chemotherapeutic agents

Jansson

Alao

Viktorsson

et al. 2013

Environ and Mol Mutagen

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The highly conserved DNA glycosylase MutY is implicated in repair of oxidative DNA damage, in particular in removing adenines misincorporated opposite 7,8-dihydro-8-oxoguanine (8-oxo-G). The MutY homologues (MutYH) physically associate with proteins implicated in replication, DNA repair, and checkpoint signaling, specifically with the DNA damage sensor complex 9-1-1 proteins. Here, we ask whether MutYH could have a broader function in sensing and repairing different types of DNA damage induced by conventional chemotherapeutics. Thus, we examined if deletion of the Schizosaccharomyces pombe MutY homologue, Myh1, alone or in combination with deletion of either component of the 9-1-1 sensor complex, influences survival after exposure to different classes of DNA damaging chemotherapeutics that do not act primarily by causing 8-oxoG lesions. We show that Myh1 contributes to survival on genotoxic stresses induced by the oxidizing, DNA double strand break-inducing, bleomycins, or the DNA crosslinking platinum compounds, particularly in a rad1 mutant background. Exposure of cells to cisplatin leads to a moderate overall accumulation of Myh1 protein. Interestingly, we found that DNA damage induced by phleomycin results in increased chromatin association of Myh1. Further, we demonstrate that Myh1 relocalizes to the nucleus after exposure to hydrogen peroxide or chemotherapeutics, most prominently seen after phleomycin treatment. These observations indicate a wider role of Myh1 in DNA repair and DNA damage-induced checkpoint activation than previously thought.

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Section: Discussionsupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

A role for Myh1 in DNA repair after treatment with strand‐breaking and crosslinking chemotherapeutic agents

Jansson

Alao

Viktorsson

et al. 2013

Environ and Mol Mutagen

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“…The authors did not offer any mechanism for MYH-dependent DNA damage response by UV damage or replication stress. In S. pombe , myh1 knockout cells confers a very mild UV and HU sensitivity [53,54]; only myh1 rad1 double mutant display enhanced sensitivity to UV and HU as compared to single mutants [54]. …”

Section: Discussionmentioning

confidence: 99%

Mammalian MutY homolog (MYH or MUTYH) protects cells from oxidative DNA damage

Hwang

Shi

2014

DNA Repair

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MutY DNA glycosylase homologs (MYH or MUTYH) reduce G:C to T:A mutations by removing misincorporated adenines or 2-hydroxyadenines paired with guanine or 7,8-dihydro-8-oxo-guanine (8-oxoG). Mutations in human the MYH (hMYH) gene are associated with the colorectal cancer predisposition syndrome MYH-associated polyposis. To examine the function of MYH in human cells, we regulated MYH gene expression by knockdown or overproduction. The hMYH knockdown human HeLa cells are more sensitive to the killing effects of H2O2 than the control cells. In addition, hMYH knockdown cells have altered cell morphology, display enhanced susceptibility to apoptosis, and have altered DNA signaling activation in response to oxidative stress. The cell cycle progression of hMYH knockdown cells is also different from that of the control cells following oxidative stress. Moreover, hMYH knockdown cells contain higher levels of 8-oxoG lesions than the control cells following H2O2 treatment. Although MYH does not directly remove 8-oxo-G, MYH may generate favorable substrates for other repair enzymes. Overexpression of mouse MYH (mMYH) in human mismatch repair defective HCT15 cells makes the cells more resistant to killing and refractory to apoptosis by oxidative stress than the cells transfected with vector. In conclusion, MYH is a vital DNA repair enzyme that protects cell from oxidative DNA damage and is critical for proper cellular response to DNA damage.

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“…On the other hand, there are a number of reports that show that loss of MUTYH actually can sensitize cells to DNA damaging agents. Along this line, double mutations in S. pombe MUTYH with RAD1 or, to a lesser extent RAD9 , were shown to enhance the sensitivity of the cells to DNA damaging agents and hydroxyurea (Jansson et al, 2008). The consequences of these deficiencies were chromosome segregation defects and checkpoint failure after UV irradiation, as well as morphological defects, even in the absence of DNA damaging agents.…”

Section: Function Of Muty and Mutyhmentioning

confidence: 99%

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

Markkanen¹,

Dorn²,

Hübscher³

2013

Front. Genet.

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Maintenance of genetic stability is crucial for all organisms in order to avoid the onset of deleterious diseases such as cancer. One of the many proveniences of DNA base damage in mammalian cells is oxidative stress, arising from a variety of endogenous and exogenous sources, generating highly mutagenic oxidative DNA lesions. One of the best characterized oxidative DNA lesion is 7,8-dihydro-8-oxoguanine (8-oxo-G), which can give rise to base substitution mutations (also known as point mutations). This mutagenicity is due to the miscoding potential of 8-oxo-G that instructs most DNA polymerases (pols) to preferentially insert an Adenine (A) opposite 8-oxo-G instead of the appropriate Cytosine (C). If left unrepaired, such A:8-oxo-G mispairs can give rise to CG→AT transversion mutations. A:8-oxo-G mispairs are proficiently recognized by the MutY glycosylase homologue (MUTYH). MUTYH can remove the mispaired A from an A:8-oxo-G, giving way to the canonical base-excision repair (BER) that ultimately restores undamaged Guanine (G). The importance of this MUTYH-initiated pathway is illustrated by the fact that biallelic mutations in the MUTYH gene are associated with a hereditary colorectal cancer syndrome termed MUTYH-associated polyposis (MAP). In this review, we will focus on MUTYH, from its discovery to the most recent data regarding its cellular roles and interaction partners. We discuss the involvement of the MUTYH protein in the A:8-oxo-G BER pathway acting together with pol λ, the pol that can faithfully incorporate C opposite 8-oxo-G and thus bypass this lesion in a correct manner. We also outline the current knowledge about the regulation of MUTYH itself and the A:8-oxo-G repair pathway by posttranslational modifications (PTM). Finally, to achieve a clearer overview of the literature, we will briefly touch on the rather confusing MUTYH nomenclature. In short, MUTYH is a unique DNA glycosylase that catalyzes the excision of an undamaged base from DNA.

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The tumor suppressor homolog in fission yeast, myh1+, displays a strong interaction with the checkpoint gene rad1+

Cited by 8 publications

References 36 publications

A role for Myh1 in DNA repair after treatment with strand‐breaking and crosslinking chemotherapeutic agents

A role for Myh1 in DNA repair after treatment with strand‐breaking and crosslinking chemotherapeutic agents

Mammalian MutY homolog (MYH or MUTYH) protects cells from oxidative DNA damage

MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA

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