DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

Chen, Xiaojiang S.; Pomerantz, Richard T.

doi:10.3390/genes12081146

Cited by 14 publications

(19 citation statements)

References 87 publications

(163 reference statements)

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“…A recent study on the fruit fly showed that TMEJ compensates for the BRCA2 dependent loss of HR on Holliday junction resolvases by using HR-intermediates that suppress mitotic crossing over and preserve the genomic stability [ 44 ]. BRCA2 deficiency has been shown to be synthetic lethal with disruption of either RAD52 or polymerase theta (POLQ) [ 26 , 27 , 45 , 46 , 47 , 48 ] or both [ 49 ]. Both RAD52 and POLQ are, therefore, important backup pathways for DSB repair and RS responses in BRCA2 deficient cells.…”

Section: Discussionmentioning

confidence: 99%

BRCA2 Haploinsufficiency in Telomere Maintenance

Gunnarsdottir

Bjarnason

Þorvaldsdóttir

et al. 2021

Genes

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Our previous studies showed an association between monoallelic BRCA2 germline mutations and dysfunctional telomeres in epithelial mammary cell lines and increased risk of breast cancer diagnosis for women with BRCA2 999del5 germline mutation and short telomeres in blood cells. In the current study, we analyzed telomere dysfunction in lymphoid cell lines from five BRCA2 999del5 mutation carriers and three Fanconi Anemia D1 patients by fluorescence in situ hybridization (FISH). Metaphase chromosomes were harvested from ten lymphoid cell lines of different BRCA2 genotype origin and analyzed for telomere loss (TL), multitelomeric signals (MTS), interstitial telomere signals (ITS) and extra chromosomal telomere signals (ECTS). TL, ITS and ECTS were separately found to be significantly increased gradually between the BRCA2+/+, BRCA2+/- and BRCA2-/- lymphoid cell lines. MTS were found to be significantly increased between the BRCA2+/+ and the BRCA2+/- heterozygous (p < 0.0001) and the BRCA2-/- lymphoid cell lines (p < 0.0001) but not between the BRCA2 mutated genotypes. Dysfunctional telomeres were found to be significantly increased in a stepwise manner between the BRCA2 genotypes indicating an effect of BRCA2 haploinsufficiency on telomere maintenance.

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Section: Discussionmentioning

confidence: 99%

BRCA2 Haploinsufficiency in Telomere Maintenance

Gunnarsdottir

Bjarnason

Þorvaldsdóttir

et al. 2021

Genes

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“…Microhomology-mediated end joining (MMEJ) and single-strand annealing (SSA) are mutagenic NHEJ-related pathways that have been reviewed in more detail elsewhere [3,29,30] and are beyond the scope of this review. It is relevant to note that MMEJ may be initiated by PARP1 [29] and is facilitated by polθ [31].…”

Section: Nonhomologous End-joiningmentioning

confidence: 99%

“…It is commonly overexpressed in many cancers, typically correlating with other HR defects and worse patient outcomes. Furthermore, overexpression of polθ has been shown to contribute to resistance to DNA-damaging agents such as radiotherapy, chemotherapy agents, and PARPi [31]. Following the discovery of a selective polθ inhibitor and using knockout models, it was identified that inhibition or loss of polθ can induce synthetic lethality in BRCA-and HR-deficient cells [31,127].…”

Section: Dna Polymerasesmentioning

confidence: 99%

“…Furthermore, overexpression of polθ has been shown to contribute to resistance to DNA-damaging agents such as radiotherapy, chemotherapy agents, and PARPi [31]. Following the discovery of a selective polθ inhibitor and using knockout models, it was identified that inhibition or loss of polθ can induce synthetic lethality in BRCA-and HR-deficient cells [31,127]. It has been suggested that polθ inhibitors may be of benefit in combination with other DNA repair inhibitors, such as PARPi and ATRi, as well as standard chemotherapy agents.…”

Section: Dna Polymerasesmentioning

confidence: 99%

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Evolving DNA repair synthetic lethality targets in cancer

et al. 2022

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DNA damage signaling response and repair (DDR) is a critical defense mechanism against genomic instability. Impaired DNA repair capacity is an important risk factor for cancer development. On the other hand, upregulation of DDR mechanisms is a feature of cancer chemotherapy and radiotherapy resistance. Advances in our understanding of DDR and its complex role in cancer has led to several translational DNA repair targeted investigations culminating in clinically viable precision oncology strategy using PARP inhibitors in breast, ovarian, pancreatic and prostate cancers. Whilst PARP directed synthetic lethality has improved outcomes for many patients, the lack of sustained clinical response and the development of resistance pose significant clinical challenges. Therefore, the search for additional DDR directed drug targets and novel synthetic lethality approaches is highly desirable and is an area of intense pre-clinical and clinical investigation. Here we provide an overview of the mammalian DNA repair pathways and then focus on current state of PARP inhibitors and other emerging DNA repair inhibitors for synthetic lethality in cancer.

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“…Given the role of DNA polymerases in DNA replication and repair, it is not surprising that any disruption or irregularity in the function of DNA polymerases can disrupt the genomic stability of an individual, thereby increasing the rate of gene mutations and an individual's vulnerability to cancer (Lange et al, 2011). Of the different DNA polymerases, DNA polymerase θ (POLQ) has become an attractive target in anti-cancer drug discovery strategies (Chen and Pomerantz, 2021). This multi-functional DNA polymerase plays a key role in tumors with deficient homologous recombination (HR).…”

Section: Introductionmentioning

confidence: 99%

DNA polymerase θ (POLQ): A druggable DNA polymerase for homologous recombination-deficient cancer cells

EDIRIWEERA¹

2023

Biocell

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Irregularities in the DNA repair pathways are frequently observed in cancer. Dysregulated DNA repair pathways support growth advantages to tumor cells. DNA polymerase-theta (POLQ) is an error-prone DNA polymerase involved in double-strand break repair through microhomology-mediated end joining (MMEJ). POLQ also mediates translesion DNA synthesis and it is largely not expressed in normal cells. POLQ is overexpressed in a range of cancer cells, including homologous recombination (HR) deficient cancer cells. In HR deficient cells, MMEJ is crucial as a backup DNA repair pathway, indicating the indispensable role of POLQ-mediated MMEJ in HR deficient cancer cells. In addition, POLQ is synthetic lethal with a number of oncogenes. This viewpoint highlights the potential role of POLQ as a new target in the treatment of HR-deficient tumors and aims to develop enthusiasm to introduce fundamental aspects of Molecular Biology and Biochemistry to basic research related to Molecular Life Sciences, Cell Biology and Genetics in Sri Lanka as Molecular Biology and Biochemistry fundamentals can still do wonders in modern research.

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DNA Polymerase θ: A Cancer Drug Target with Reverse Transcriptase Activity

Cited by 14 publications

References 87 publications

BRCA2 Haploinsufficiency in Telomere Maintenance

BRCA2 Haploinsufficiency in Telomere Maintenance

Evolving DNA repair synthetic lethality targets in cancer

DNA polymerase θ (POLQ): A druggable DNA polymerase for homologous recombination-deficient cancer cells

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