Association between newly identified variant form of DNA polymerase betaΔ208–304 and ovarian cancer

Khanra, Kalyani; Panda, Kakali; Bhattacharya, Chandan; Mitra, Arnab; Sarkar, Ranu; Banerjee, Sipra; Bhattacharyya, Nandan

doi:10.3233/cbm-2012-00275

Cited by 7 publications

(5 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in polβ may influence aggressive solid tumour phenotype and response to chemotherapy [13]. In ovarian cancers, mutations in polβ have been recognised [41] although clinical significance remains unclear [41]. In clinical cohorts of ovarian cancers, we show that low Polβ expression is associated with better PFS.…”

Section: Discussionmentioning

confidence: 75%

Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

et al. 2021

View full text Add to dashboard Cite

Targeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.

show abstract

Section: Discussionmentioning

confidence: 75%

Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In our previous study, we found an ovarian cancer-specific mutation in the DNA Polβ, with the deletion in the catalytic domain [ 9 ]. This mutated protein (PolβΔ) was co-expressed with wild-type Polβ in heterozygous conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Nucleotide sequences of the Polβ and PolβΔ were used from our previously published literature [ 9 ], provided in Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

“…Several enzymes involved in the BER pathway interact with Polβ like DNA glycosylase, APE, PKNP, FEN1, PARP, XRCC1, [ 8 ] etc. In our previous study, we reported an ovarian cancer-specific mutation in the DNA Polβ, with the deletion in exon number 11–13, which could be detectable at an earlier stage of cancer [ 9 ]. This mutation was found in the catalytic part of the Polβ.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

PA1 cells containing a truncated DNA polymerase β protein are more sensitive to gamma radiation

Patra¹,

Nag

Chakraborty

et al. 2022

Radiat Oncol J

Self Cite

View full text Add to dashboard Cite

Purpose: DNA polymerase β (Polβ) acts in the base excision repair (BER) pathway. Mutations in DNA polymerase β (Polβ) are associated with different cancers. A variant of Polβ with a 97 amino acid deletion (PolβΔ), in heterozygous conditions with wild-type Polβ, was identified in sporadic ovarian tumor samples. This study aims to evaluate the gamma radiation sensitivity of PolβΔ for possible target therapy in ovarian cancer treatment.Materials and Methods: PolβΔ cDNA was cloned in a GFP vector and transfected in PA1 cells. Stable cells (PA1PolβΔ) were treated with 60Co sourced gamma-ray (0–15 Gy) to investigate their radiation sensitivity. The affinity of PolβΔ with DNA evaluated by DNA protein in silico docking experiments.Result: The result showed a statistically significant (p < 0.05) higher sensitivity towards radiation at different doses (0–15 Gy) and time-point (48–72 hours) for PA1PolβΔ cells in comparison with normal PA1 cells. Ten Gy of gamma radiation was found to be the optimal dose. Significantly more PA1PolβΔ cells were killed at this dose than PA1 cells after 48 hours of treatment via an apoptotic pathway. The in silico docking experiments revealed that PolβΔ has more substantial binding potential towards the dsDNA than wild-type Polβ, suggesting a possible failure of BER pathway that results in cell death.Conclusion: Our study showed that the PA1PolβΔ cells were more susceptible than PA1 cells to gamma radiation. In the future, the potentiality of ionizing radiation to treat this type of cancer will be checked in animal models.

show abstract

“…Mutations in Pol β are also highly linked to lung, breast, bladder, and esophageal cancers [6]. Khana et al [7][8][9][10][11] explored various Pol β mutations associated with ovarian cancers. Ovarian cancer is a signi cant health concern among Indian women, ranking as the third most common cancer and the eighth most prevalent overall in the country.…”

Section: Introductionmentioning

confidence: 99%

Exploring phytochemical as potential inhibitors of human DNA polymerase β for targeted ovarian cancer therapy: An In-Silico approach.

Patra,

Choudhuri,

Paria

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Ovarian cancer poses significant challenges due to limited treatment options and high mortality rates, necessitating innovative therapeutic strategies. Targeting DNA repair pathways, such as DNA polymerase β (Pol β), holds promise for improving treatment outcomes. This study aims to identify phytochemicals from the SuperNatural database as natural inhibitors of Pol β activity to enhance ovarian cancer therapy efficacy, particularly when used in combination with damaging agents. Screening 21,105 drug-like molecules and 800 NatProd molecules based on Lipinski's rule of five, Golden Triangle rule, and Pfizer’s rule, followed by the removal of compounds with predicted carcinogenicity, toxicity, and mutagenicity, resulted in 1,104 molecules for structure-based virtual screening. Docking-based virtual screening using two servers was conducted on selected molecules, followed by computer simulations to assess their interaction dynamics and stability with Pol β. Molecular dynamics simulations further evaluated stability and interactions, considering energy, forces, and interaction scores. From these analyses, four promising Pol β inhibitors—SN00158342, SN00305418, SN00004251, and SN00341636—were identified, exhibiting favorable stability profiles and interactions. Utilizing these compounds alongside DNA-damaging agents presents a novel and potentially fruitful approach to improving ovarian cancer treatment outcomes. Overall, this study underscores the potential of phytochemicals as effective Pol β inhibitors, offering a promising avenue for enhancing ovarian cancer therapy effectiveness.

show abstract

Association between newly identified variant form of DNA polymerase betaΔ208–304 and ovarian cancer

Abstract: The result reveals that this variant form of polβ is a predisposing factor for stage IV ovarian cancer samples in Indian population.

Cited by 7 publications

References 22 publications

Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

PA1 cells containing a truncated DNA polymerase β protein are more sensitive to gamma radiation

Exploring phytochemical as potential inhibitors of human DNA polymerase β for targeted ovarian cancer therapy: An In-Silico approach.

Contact Info

Product

Resources

About