Nuclear translocation contributes to regulation of DNA excision repair activities

Knudsen, Nils; Andersen, Steen; Lützen, Anne; Nielsen, Finn Cilius; Rasmussen, Lene Juel

doi:10.1016/j.dnarep.2009.03.005

Cited by 43 publications

(49 citation statements)

References 105 publications

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“…40,41 MSH2 does not contain a clear nuclear localization signal and is largely dependent on MSH6 for co-import into the nucleus. 44,45 It has previously been shown that there is a movement of the cytoplasmic MSH2 into the nucleus on the induction of DNA damage. 40,41 In keeping with the concept that NPM-ALK disrupts the MSH2·MSH6 interaction, we found evidence that NPM-ALK also interfere with the MSH2 nuclear translocation on DNA damage, as shown in Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…40,41 Considering that NPM-ALK interfered with the MSH2·MSH6 binding and that heterodimerization with MSH6 is required for effective nuclear import of MSH2, 44,45 we asked whether NPM-ALK affected this normal MMR response to DNA adducts. Using the Tet-on HEK293/NPM-ALK cells, we performed subcellular fractionation following exposure to 6TG.…”

Section: Npm-alk Impedes the Dna Adduct-induced Relocalization Of Msh2mentioning

confidence: 99%

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Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

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The fusion tyrosine kinase NPM-ALK is central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK ؉ ALCL). We recently identified that MSH2, a key DNA mismatch repair (MMR) protein integral to the suppression of tumorigenesis, is an NPM-ALK-interacting protein. In this study, we found in vitro evidence that enforced expression of NPM-ALK in HEK293 cells suppressed MMR function. Correlating with these findings, six of nine ALK ؉ ALCL tumors displayed evidence of microsatellite instability, as opposed to none of the eight normal DNA control samples (P ‫؍‬ 0.007, Student's t-test). Using co-immunoprecipitation, we found that increasing levels of NPM-ALK expression in HEK293 cells resulted in decreased levels of MSH6 bound to MSH2, whereas MSH2·NPM-ALK binding was increased. The NPM-ALK·MSH2 interaction was dependent on the activation/autophosphorylation of NPM-ALK, and the Y191 residue of NPM-ALK was a crucial site for this interaction and NPM-ALK-mediated MMR suppression. MSH2 was found to be tyrosine phosphorylated in the presence of NPM-ALK. Finally, NPM-ALK impeded the expected DNA damage-induced translocation of MSH2 out of the cytoplasm. To conclude, our data support a model in which the suppression of MMR by NPM-ALK is attributed to its ability to interfere with normal MSH2 biochemistry and function.

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Section: Discussionmentioning

confidence: 99%

Section: Npm-alk Impedes the Dna Adduct-induced Relocalization Of Msh2mentioning

confidence: 99%

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Young

Bone

Wang

et al. 2011

The American Journal of Pathology

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“…Briefly, the repair process is initiated by one of several DNA glycosylases, each recognizing a specific DNA lesion (e.g. OGG1, NTH, NEIL and MYH recognize oxidation damage; deamination damages are recognized by UDG, MED1, UNG, and TDG, and MPG initiate alkylation repair) (Knudsen et al, 2009). These DNA glycosylases excise the damaged base (by cleave of N-glycosidic bond between the sugar and the base), generating an AP site.…”

Section: Base Excision Repairmentioning

confidence: 99%

“…Protein expression, pos-translational modifications and nuclear translocation of DNA repair proteins have been referred as essential in the regulation of DNA repair activity and to maintain genomic stability. However, these subjects need to be clarified in the future (Knudsen et al, 2009;Tudek, 2007). When DNA damage is not repaired, the cell by a complex network that collectively forms the DNA damage response (DDR) machinery delays cell-cycle progression, acting on cell cycle checkpoints.…”

Section: Introductionmentioning

confidence: 99%

“…In this regard, Endonuclease III, FPG and AlkA have been used to detect oxidized pyrimidines, modified purines and alkylpurines bases, respectively. With these repair proteins from different repair pathways, suggesting that regulation of DNA repair involves protein cross-talk (Knudsen et al, 2009). Protein expression, pos-translational modifications and nuclear translocation of DNA repair proteins have been referred as essential in the regulation of DNA repair activity and to maintain genomic stability.…”

Section: Introductionmentioning

confidence: 99%

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DNA Damage Protection and Induction of Repair by Dietary Phytochemicals and Cancer Prevention: What Do We Know?

Ramos¹,

Lima²,

Pereira‐Wilson³

2011

Selected Topics in DNA Repair

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Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG

et al. 2023

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Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin β‐mediated cytoplasmic–nuclear protein translocation. Its deregulation may thus alter the functionality of cancer‐relevant nuclear proteins, such as the base excision repair (BER) enzyme N‐methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated‐H2AX‐positive cells upon treatment with an alkylating agent. This suggested reduced MPG‐mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment‐related lesions and contributing to treatment resistance.

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Nuclear translocation contributes to regulation of DNA excision repair activities

Cited by 43 publications

References 105 publications

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

Fusion Tyrosine Kinase NPM-ALK Deregulates MSH2 and Suppresses DNA Mismatch Repair Function

DNA Damage Protection and Induction of Repair by Dietary Phytochemicals and Cancer Prevention: What Do We Know?

Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG

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