Polymerase iota - an odd sibling among Y family polymerases

McIntyre, Justyna

doi:10.1016/j.dnarep.2019.102753

Cited by 30 publications

(33 citation statements)

References 172 publications

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“…Thus, it is urgent to understand how ESCC progresses in order to improve its clinical outcomes. DNA polymerase iota (Pol i) belongs to the Y-family DNA polymerase and participates in translesion DNA synthesis (TLS) (8). Pol i (product of the POLI gene) was identified as the second homolog of yeast Rad30 gene in human (9).…”

Section: Introductionmentioning

confidence: 99%

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Gao

et al. 2021

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancers with rapid progression and a high mortality rate. Our previous study demonstrated that DNA polymerase iota (Pol ι) is overexpressed in ESCC tumors and correlates with poor prognosis. However, its role in ESCC proliferation remains obscure. We report here that Pol ι promotes ESCC proliferation and progression through Erk- O-GlcNAc transferase (OGT) regulated Glucose-6-phosphate dehydrogenase (G6PD) overactivation. Cell clonogenic ability was assessed by colony formation assay. Cell proliferation was assessed by EdU incorporation assay. Our transcriptome data was reanalyzed by GSEA and validated by analysis of cellular metabolism, G6PD activity, and cellular NADPH concentration. The level of Pol ι, OGT, G6PD and O-GlcNAcylation in ESCC cells and patient samples were analyzed. The MEK inhibitor PD98059 was applied to confirm OGT expression regulation by the Erk signaling. The G6PD inhibitor polydatin was used to examine the role of G6PD activation in Pol ι promoted proliferation. We found that Pol ι promotes ESCC proliferation. It shunted the glucose flux towards the pentose phosphate pathway (PPP) by activating G6PD through OGT-promoted O-GlcNAcylation. The expression of OGT was positively correlated with Pol ι expression and O-GlcNAcylation. Notably, elevated O-GlcNAcylation was correlated with poor prognosis in ESCC patients. Pol ι was shown to stimulate Erk signaling to enhance OGT expression, and the G6PD inhibitor polydatin attenuated Pol ι induced tumor growth in vitro and in vivo. In conclusion, Pol ι activates G6PD through Erk-OGT-induced O-GlcNAcylation to promote the proliferation and progression of ESCC, supporting the notion that Pol ι is a potential biomarker and therapeutic target of ESCC.

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Section: Introductionmentioning

confidence: 99%

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

Gao

et al. 2021

Front. Oncol.

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“…One distinctive feature of Pol ι is an unusual catalytic pocket that prefers Hoogsteen over Watson-Crick pairing (73), which may accommodate a broader spectrum of lesions. Indeed, Pol ι has been shown to be able to bypass bulky adducts that are unable to be bypassed by other translesion synthesis (TLS) polymerases (74). Furthermore, in the presence of Mn 2+ , Pol ι is able to bypass a peptide adduct that mimics the DNA-protein crosslink repair intermediate (75,76).…”

Section: Discussionmentioning

confidence: 99%

DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress

Wang

Lenoir

Wang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Fanconi anemia (FA) is caused by defects in cellular responses to DNA crosslinking damage and replication stress. Given the constant occurrence of endogenous DNA damage and replication fork stress, it is unclear why complete deletion of FA genes does not have a major impact on cell proliferation and germ-line FA patients are able to progress through development well into their adulthood. To identify potential cellular mechanisms that compensate for the FA deficiency, we performed dropout screens in FA mutant cells with a whole genome guide RNA library. This uncovered a comprehensive genome-wide profile of FA pathway synthetic lethality, including POLI and CDK4. As little is known of the cellular function of DNA polymerase iota (Pol ι), we focused on its role in the loss-of-function FA knockout mutants. Loss of both FA pathway function and Pol ι leads to synthetic defects in cell proliferation and cell survival, and an increase in DNA damage accumulation. Furthermore, FA-deficient cells depend on the function of Pol ι to resume replication upon replication fork stalling. Our results reveal a critical role for Pol ι in DNA repair and replication fork restart and suggest Pol ι as a target for therapeutic intervention in malignancies carrying an FA gene mutation.

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“…Notably, POL η is overexpressed in head and neck squamous cell carcinoma (HNSCC) [87], POL θ expression is associated with poor patient survival in breast cancer [88], and POL κ is overexpressed in glioblastoma and lung cancer patients [89][90][91]. Additionally, POL ι expression is tightly correlated with cancer incidence in esophageal squamous cell carcinoma [92][93][94][95]. Further evidence for elevated TLS activity comes from whole-genome sequencing in cancers in which TLS specific mutational signatures are consistent with the upregulation of POL η and POL ε.…”

Section: Tls a Cancer Adaptationmentioning

confidence: 99%

Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability

Nayak

Calvo

Cantor

2021

Expert Opinion on Therapeutic Targets

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Polymerase iota - an odd sibling among Y family polymerases

Cited by 30 publications

References 172 publications

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

DNA Polymerase Iota Promotes Esophageal Squamous Cell Carcinoma Proliferation Through Erk-OGT-Induced G6PD Overactivation

DNA polymerase ι compensates for Fanconi anemia pathway deficiency by countering DNA replication stress

Targeting translesion synthesis (TLS) to expose replication gaps, a unique cancer vulnerability

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