Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells

Bostian, April C.L.; Maddukuri, Leena; Reed, Megan R.; Savenka, Tatsiana; Hartman, Jessica H.; Davis, Lauren Evoy; Pouncey, Dakota L.; Miller, Grover P.; Eoff, Robert L.

doi:10.1021/acs.chemrestox.5b00452

Cited by 32 publications

(53 citation statements)

References 42 publications

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“…The loss of pChk1 signal that accompanied TDO inhibition is interesting given that hpol k has been shown to help activate the Rad17-arm of the ATR signaling cascade leading to phosphorylation of the Chk1 kinase. Previously we observed down-regulation of hpol k in response to TDO inhibition (13). In this respect, the reduction in pS345 Chk1 when TDO was inhibited might be due to suppression of hpol k/Rad17-mediated activation of ATR (16,17).…”

Section: Inhibition Of Tdo Leads To Diminished Resolution Of Rs Inducmentioning

confidence: 79%

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Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Reed

Maddukuri

Ketkar

et al. 2020

Preprint

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Aberrant expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy and immune response in gliomas in part through kynurenine (KYN)-mediated activation of the aryl hydrocarbon receptor (AhR). In the current study, we investigated the hypothesis that TDO activation in gliomas has a broad impact upon genome maintenance -promoting tolerance of replication stress (RS) and repair of DNA damage. We report that inhibition of TDO activity attenuated recovery from hydroxyurea (HU)-induced RS and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU), as fork progress was impeded when TDO-deficient glioma cells were treated with BCNU. Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to treatment with BCNU, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced -indicative of increased fork collapse. Restoration of KYN levels protected against some replication-associated effects of BCNU. Inhibition of TDO activity had a strong anti-proliferative effect on glioma-derived cells -enhancing the cytotoxic effects of BCNU. Analysis of results obtained using quantitative proteomics revealed TDOdependent changes in several signaling pathways -including down-regulation of DNA repair factors and sirtuin signaling. Consistent with these observations, inhibition of TDO diminished SIRT7 recruitment to chromatin, which increased histone H3K18 acetylation -a key mark involved in 53BP1 recruitment to sites of DNA damage. Cells lacking TDO activity exhibited defective recruitment of 53BP1 to gH2AX foci, which corresponded with delayed repair of BCNU-induced DNA breaks. Addition of exogenous KYN increased the rate of break repair. The discovery that TDO activity modulates sensitivity to DNA damage by fueling SIRT7/53BP1 localization to chromatin and repair of BCNU-induced DNA damage highlights the potential for tumor-specific metabolic changes to influence genome stability and may have implications for glioma biology and treatment strategies.

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Section: Inhibition Of Tdo Leads To Diminished Resolution Of Rs Inducmentioning

confidence: 79%

“…Previously, we showed that modulation of the KP affected the expression of the translesion synthesis (TLS) enzyme DNA polymerase kappa (hpol k) (13). Treating GBM-derived cell lines with an inhibitor of TDO lowered hpol k expression and led to a diminished level of micronuclei (MN).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Reed

Maddukuri

Ketkar

et al. 2020

Preprint

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“…The oncological relevance of pol κ and pol η in cancer is most firmly established concerning response to treatment. Upregulation of pol κ confers resistance to temozolomide in glioblastoma, 34,35 and upregulation of pol η to platinum drugs in HNSCC, lung, gastric adenocarcinomas, and ovarian cancers. [36][37][38] Contrary to our results, low levels of POLK were previously observed in CRC.…”

Section: Associations Of Dsbr Iclr and Ddt/tls Key Components Witmentioning

confidence: 99%

The role of double‐strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression—clinicopathological data and survival

Laporte

Leguisamo

Glória

et al. 2019

Journal of Surgical Oncology

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Background and Objectives DNA repair is a new and important pathway that explains colorectal carcinogenesis. This study will evaluate the prognostic value of molecular modulation of double‐strand break repair (XRCC2 and XRCC5); DNA damage tolerance/translesion synthesis (POLH, POLK, and POLQ), and interstrand crosslink repair (DCLRE1A) in sporadic colorectal cancer (CRC). Methods Tumor specimens and matched healthy mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ, and DCLRE1A; protein expression of Polk, Ku80, p53, Ki67, and mismatch repair MLH1 and MSH2 components; CpG island promoter methylation of XRCC5, POLH, POLK, POLQ, and DCLRE1A was performed. Results Neoplastic tissues exhibited induction of POLK (P < .001) and DCLRE1A (P < .001) expression and low expression of POLH (P < .001) and POLQ (P < .001) in comparison to healthy paired mucosa. Low expression of POLH was associated with mucinous histology and T1‐T2 tumors (P = .038); low tumor expression of POLK was associated with distant metastases (P = .042). CRC harboring POLK promoter methylation exhibited better disease‐free survival (DFS) (P = .005). Conclusions This study demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylation was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.

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“…113 Furthermore, blocking KYN signaling in GBM-derived cells with a small-molecule inhibitor of TDO (680C91) led to a dramatic decrease in hpol κ protein levels. 113 …”

Section: Kyn Activation Of Ahr Promotes Up-regulation Of Hpol κmentioning

confidence: 99%

“…TDO activity -> AhR signaling -> hpol κ expression). 113 It is reasonable to assume that KYN signaling will be found to affect additional DNA damage and replication stress response factors. If such an assumption proves true, then it would go some way towards explaining why blocking KYN signaling has been found to act synergistically with genotoxic anti-cancer drugs in multiple models of cancer.…”

Section: Kyn Activation Of Ahr Promotes Up-regulation Of Hpol κmentioning

confidence: 99%

Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas

Bostian

Eoff

2016

Chem. Res. Toxicol.

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Metabolism of the essential amino acid L-tryptophan (TRP) is implicated in a number of neurological conditions including depression, neurodegenerative diseases, and cancer. The TRP catabolite kynurenine (KYN) has recently emerged as an important neuroactive factor in brain tumor pathogenesis, with additional studies implicating KYN in other types of cancer. Often highlighted as a modulator of the immune response and a contributor to immune escape for malignant tumors, it is well known that KYN has effects on the production of the co-enzyme nicotinamide adenine dinucleotide (NAD+), which can have a direct impact on DNA repair, replication, cell division, redox signaling, and mitochondrial function. Additional effects of KYN signaling are imparted through its role as an endogenous agonist for the aryl hydrocarbon receptor (AhR), and it is largely through activation of the AhR that KYN appears to mediate malignant progression in gliomas. We have recently reported on the ability of KYN signaling to modulate expression of human DNA polymerase kappa (hpol κ), a translesion enzyme involved in bypass of bulky DNA lesions and activation of the replication stress response. Given the impact of KYN on NAD+ production, AhR signaling, and translesion DNA synthesis, it follows that dysregulation of KYN signaling in cancer may promote malignancy through alterations in the level of endogenous DNA damage and replication stress. In the following perspectives article, we discuss the connections between KYN signaling, DNA damage tolerance, and genomic instability, as they relate to cancer.

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Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells

Cited by 32 publications

References 42 publications

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

The role of double‐strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression—clinicopathological data and survival

Aberrant Kynurenine Signaling Modulates DNA Replication Stress Factors and Promotes Genomic Instability in Gliomas

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