The Pathways of Double-Strand Break Repair

Mladenov, Emil; Iliakis, George

doi:10.5772/24572

Cited by 3 publications

(4 citation statements)

References 140 publications

(155 reference statements)

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“…The repair mechanism is initiated when the DNA double-strand breaks occur, and includes homologous recombination or NHEJ (45,46). If excessive damage occurs, this may cause the repair processes to proceed incompletely and to be dominated by the NHEJ mechanism, which is considered an error-prone repair pathway (29). A potential explanation for this is that the NHEJ mechanism of repair can take place throughout the cell cycle and does not require any specific template.…”

Section: Discussionmentioning

confidence: 99%

“…Physiological or pathological processes can cause DNA double-strand breaks to occur. Physiological processes that cause DNA double-strand breaks comprise v(D)J recombination, class-switch recombination, meiosis or DNA replication, in which DNA double-strand breaks occur as a secondary event during the normal cell cycle (29). DNA double-strand breaks can also occur due to exposure to ionizing radiation, oxidizing free radicals, enzymatic processes or cytotoxic agents (30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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High concentration of γ‑H2AX correlates with a marker of apoptotic suppression and PI3K/Akt pathway upregulation in glioblastoma multiforme

et al. 2023

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Glioblastoma multiforme (GBM) is a very aggressive type of primary brain tumor in adults with a poor prognosis. DNA double-strand breaks are known to be associated with the development of numerous cancer types due to their ability to generate genomic instabilities. In GBM, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is a common pathway that can be activated by exogenous and endogenous factors. Genomic instability may be an endogenous stimulating factor for activation of the PI3K/Akt pathway, which may inhibit the apoptosis of GBM cells. Spontaneous DNA double-strand breaks play an essential role in the survival of GBM cells, and apoptosis levels may reflect survival ability. However, no study has yet been conducted to analyse the association between spontaneous DNA double-strand breaks and apoptosis in patients with GBM prior to treatment. Therefore, the present study examined the concentrations of γ-histone 2AX (γ-H2AX), a sensitive marker of spontaneous DNA double-strand breaks, and cleaved caspase-3, a marker of apoptosis, in patients with GBM. The correlation of γ-H2AX with cleaved caspase-3, PI3K and Akt was also investigated. A total of 26 pre-treatment tumor tissue specimens from patient with GBM were analyzed to determine the concentrations of γ-H2AX, PI3K, Akt and cleaved caspase-3 using sandwich enzyme-linked immunosorbent assays. The results showed a moderate positive correlation between γ-H2AX and PI3K (r=0.52; P=0.007), a moderate positive correlation between γ-H2AX and Akt (r=0.4; P=0.041) and a strong negative correlation between γ-H2AX and cleaved caspase-3 (r=-0.61; P=0.0009). These analyses were also performed in seven tumor tissue specimens from patients with grade I glioma as controls, but no significant correlations were detected. The findings of the present study suggest that a high level of γ-H2AX may affect GBM cell apoptosis via the PI3K/Akt pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

High concentration of γ‑H2AX correlates with a marker of apoptotic suppression and PI3K/Akt pathway upregulation in glioblastoma multiforme

et al. 2023

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“…All the data above suggested that VERO cells were repairing DSBs induced by BLEO via a mechanism that was independent of PARPs-1/2 and 3 since OLA can block their enzymatic activity or induce enzyme trapping. According to some authors [8,58], PARP-1 activation participates in MMEJ but not on HR or c-NHEJ. If this was the case, then the simultaneous block of HR and c-NHEJ should leave the cells dependent on MMEJ, thus dependent on PARP-1.…”

Section: Ola Did Not Potentiate Bleo Even In the Presence Of A Pool mentioning

confidence: 99%

“…The latter does not involve DNA-PK, 53BP1, or LigIV but is dependent on LigIII instead. These pathways are quite complex and MMEJ is still poorly understood [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

Perini

Schacke

Liddle

et al. 2020

IJMS

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Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested.

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Computational modeling and a Geant4-DNA study of the rejoining of direct and indirect DNA damage induced by low energy electrons and carbon ions

Mokari¹,

Moeini

Farazmand

2023

International Journal of Radiation Biology

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The Pathways of Double-Strand Break Repair

Cited by 3 publications

References 140 publications

High concentration of γ‑H2AX correlates with a marker of apoptotic suppression and PI3K/Akt pathway upregulation in glioblastoma multiforme

High concentration of γ‑H2AX correlates with a marker of apoptotic suppression and PI3K/Akt pathway upregulation in glioblastoma multiforme

PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

Computational modeling and a Geant4-DNA study of the rejoining of direct and indirect DNA damage induced by low energy electrons and carbon ions

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