Depletion of RNASEH2 Activity Leads to Accumulation of DNA Double-strand Breaks and Reduced Cellular Survivability in T Cell Leukemia

Ghosh, Debanjan; Kumari, Susmita; Raghavan, Sathees C.

doi:10.1016/j.jmb.2022.167617

Cited by 8 publications

(3 citation statements)

References 68 publications

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“…The Mycoplasma test was conducted in the laboratory using the MYCOseq kit (Thermo Fisher Scientific, Waltham, Massachusetts) and further validated by DNA labs India, Hyderabad, India. Cells were cultured in RPMI1640 or MEM medium supplemented with 10–15% fetal bovine serum (FBS), 100 μg/ml Penicillin, and 100 μg/ml streptomycin and incubated at 37 °C in a humidified atmosphere containing 5% CO 2 as described before ( Ghosh et al, 2022 ; Kumari et al, 2021 ). Rho(0) cells of B16 cells origin were cultured in DMEM medium supplemented with 15% fetal bovine serum (FBS), 100 μg/ml Penicillin, 100 μg/ml streptomycin, 50 mg/ml Uridine and 1 mM Sodium pyruvate and incubated as described above ( Dong et al, 2017 ; Tan et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

Unleashing a novel function of Endonuclease G in mitochondrial genome instability

Dahal

Siddiqua

Sharma

et al. 2022

eLife

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Having its genome makes the mitochondrion a unique and semiautonomous organelle within cells. Mammalian mitochondrial DNA (mtDNA) is a double-stranded closed circular molecule of about 16 kb coding for 37 genes. Mutations, including deletions in the mitochondrial genome, can culminate in different human diseases. Mapping the deletion junctions suggests that the breakpoints are generally seen at hotspots. '9-bp deletion' (8271-8281), seen in the intergenic region of cytochrome c oxidase II/tRNALys, is the most common mitochondrial deletion. While it is associated with several diseases like myopathy, dystonia, and hepatocellular carcinoma, it has also been used as an evolutionary marker. However, the mechanism responsible for its fragility is unclear. In the current study, we show that Endonuclease G, a mitochondrial nuclease responsible for nonspecific cleavage of nuclear DNA during apoptosis, can induce breaks at sequences associated with '9-bp deletion' when it is present on a plasmid or in the mitochondrial genome. Through a series of in vitro and intracellular studies, we show that Endonuclease G binds to G-quadruplex structures formed at the hotspot and induces DNA breaks. Therefore, we uncover a new role for Endonuclease G in generating mtDNA deletions, which depends on the formation of G4 DNA within the mitochondrial genome. In summary, we identify a novel property of Endonuclease G, besides its role in apoptosis and the recently described elimination of paternal mitochondria during fertilisation.

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Section: Methodsmentioning

confidence: 99%

Unleashing a novel function of Endonuclease G in mitochondrial genome instability

Dahal

Siddiqua

Sharma

et al. 2022

eLife

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“…The extent of RNASEH2B loss required to sensitize to PARPi remains unknown, with studies primarily demonstrating sensitivity in CRISPR knockouts with complete loss of RNASEH2 function (11)(12)(13). One study reported double strand breaks (DSB), impaired non-homologous end joining (NHEJ) and increased apoptotic cell death on small hairpin RNA depletion of both RNASEH2A and RNASEH2B in cell lines (30) suggesting that incomplete RNASEH2 loss can impact PARPi sensitivity, with at least one study in chronic lymphatic leukemia (CLL) models suggesting that monoallelic loss may sensitize to PARPi (11). Within mCRPC patients treated with the PARPi olaparib in the TOPARP trials, we show herein that there are clonal dynamics within the RNASEH2B cell population.…”

Section: Rnaseh2b In Advanced Prostate Cancer 12mentioning

confidence: 99%

RNASEH2B loss and PARP inhibition in advanced prostate cancer

Carmichael,

Figueiredo,

Gurel

et al. 2024

Journal of Clinical Investigation

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“…RNAse H1 does not induce double-stranded nicks, while RNAse H2 cleavage sites necessitate repair [ 125 ]. In consequence, the reduction of RNAse H2 led to cell cycle arrest and double-strand breaks in leukemia cells directly while also sensitizing cancer cells to radiation and other DNA damage-inducing agents [ 126 ].…”

Section: R-loops As Targets For Anticancer Drugs To Combat Chemoresis...mentioning

confidence: 99%

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

Elsakrmy

Cui

2023

IJMS

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R-loops are three-stranded DNA/RNA hybrids that form by the annealing of the mRNA transcript to its coding template while displacing the non-coding strand. While R-loop formation regulates physiological genomic and mitochondrial transcription and DNA damage response, imbalanced R-loop formation can be a threat to the genomic integrity of the cell. As such, R-loop formation is a double-edged sword in cancer progression, and perturbed R-loop homeostasis is observed across various malignancies. Here, we discuss the interplay between R-loops and tumor suppressors and oncogenes, with a focus on BRCA1/2 and ATR. R-loop imbalances contribute to cancer propagation and the development of chemotherapy drug resistance. We explore how R-loop formation can cause cancer cell death in response to chemotherapeutics and be used to circumvent drug resistance. As R-loop formation is tightly linked to mRNA transcription, their formation is unavoidable in cancer cells and can thus be explored in novel cancer therapeutics.

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Depletion of RNASEH2 Activity Leads to Accumulation of DNA Double-strand Breaks and Reduced Cellular Survivability in T Cell Leukemia

Cited by 8 publications

References 68 publications

Unleashing a novel function of Endonuclease G in mitochondrial genome instability

Unleashing a novel function of Endonuclease G in mitochondrial genome instability

RNASEH2B loss and PARP inhibition in advanced prostate cancer

R-Loops and R-Loop-Binding Proteins in Cancer Progression and Drug Resistance

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