KU70/80, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation

Abe, Takuya; Ishiai, Masamichi; Hosono, Yoshifumi; Yoshimura, Akari; Tada, Shusuke; Adachi, Noritaka; Koyama, Hideki; Takata, Minoru; Takeda, Shunichi; Enomoto, Takemi; Seki, Masayuki

doi:10.1016/j.cellsig.2008.07.006

Cited by 43 publications

(36 citation statements)

References 50 publications

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“…The increase in DNA lesions and γH2AX levels correlated with decreased viability after etoposide treatment for 48 h (Fig. 1D), as previously described (Abe et al, 2008). Accordingly, we found that α-cateninknockdown cells were less viable than wild-type cells.…”

Section: Resultssupporting

confidence: 68%

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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α-Catenin is an F-actin-binding protein widely recognized for its role in cell-cell adhesion. However, a growing body of literature indicates that α-catenin is also a nuclear protein. In this study, we show that α-catenin is able to modulate the sensitivity of cells to DNA damage and toxicity. Furthermore, nuclear α-catenin is actively recruited to sites of DNA damage. This recruitment occurs in a β-catenindependent manner and requires nuclear actin polymerization. These findings provide mechanistic insight into the WNT-mediated regulation of the DNA damage response and suggest a novel role for the α-catenin-β-catenin complex in the nucleus.

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Section: Resultssupporting

confidence: 68%

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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“…The topoisomerase II inhibitor etoposide provokes DSBs, as well as the rapid activation of ATM, ATR, DNA-PK and their corresponding substrates. [24][25][26] Exposing E14.5 retinas to etoposide in organotypic culture increased the accumulation of gH2AX and total p53 (Figure 3a), two common substrates of ATM, ATR and DNA-PK, 13,14,16 and indicative of the response of retinal cells to a genotoxic agent. Chk1, which is primarily activated by ATR, 16,27 also seemed to be phosphorylated in etoposide-treated retinas.…”

Section: Resultsmentioning

confidence: 99%

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

2010

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Programmed cell death is a crucial process in neural development that affects mature neurons and glial cells, as well as proliferating precursors and recently born neurons at earlier stages. However, the regulation of the early phase of neural cell death and its function remain relatively poorly understood. In mouse models defective in homologous recombination or nonhomologous end-joining (NHEJ), which are both DNA double-strand break (DSB) repair pathways, there is massive cell death during neural development, even leading to embryonic lethality. These observations suggest that natural DSBs occur frequently in the developing nervous system. In this study, we have found that several components of DSB repair pathways are activated in the developing mouse retina at stages that coincide with the onset of neurogenesis. In short-term organotypic retinal cultures, we confirmed that the repair pathways can be modulated pharmacologically. Indeed, inhibiting the DNA-dependent protein kinase (DNA-PK) catalytic subunit, which is involved in NHEJ, with NU7026 increased caspase-dependent cell death and selectively reduced the neuron population. This observation concurs with an increase in the number of apoptotic neurons found after NU7026 treatment, as also observed in the embryonic scid mouse retina, a mutant that lacks DNA-PK catalytic subunit activity. Therefore, our results implicate the generation of DSB and DNA-PK-mediated repair in neurogenesis in the developing retina.

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“…Etp is a topoisomerase II inhibitor that causes DNA DSBs that are mainly repaired by Artemis-independent NHEJ (49), even in the S-G 2 phase of the cell cycle (50). NHEJ-deficient DT40 cells are sensitive to Etp (51). GANP O/E rendered DT40 B cells more sensitive to Etp (Fig.…”

Section: Ganp Augments Igv L Shm In Dt40 B Cellsmentioning

confidence: 99%

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

Eid

Maeda

Almofty

et al. 2014

The Journal of Immunology

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RNA export factor germinal center–associated nuclear protein (GANP) interacts with activation-induced cytidine deaminase (AID) and shepherds it from the cytoplasm to the nucleus and toward the IgV region loci in B cells. In this study, we demonstrate a role for GANP in the repair of AID-initiated DNA damage in chicken DT40 B cells to generate IgV region diversity by gene conversion and somatic hypermutation. GANP plays a positive role in IgV region diversification of DT40 B cells in a nonhomologous end joining–proficient state. DNA-PKcs physically interacts with GANP, and this interaction is dissociated by dsDNA breaks induced by a topoisomerase II inhibitor, etoposide, or AID overexpression. GANP affects the choice of DNA repair mechanism in B cells toward homologous recombination rather than nonhomologous end joining repair. Thus, GANP presumably plays a critical role in protection of the rearranged IgV loci by favoring homologous recombination of the DNA breaks under accelerated AID recruitment.

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KU70/80, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation

Cited by 43 publications

References 50 publications

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

DNA-PK promotes the survival of young neurons in the embryonic mouse retina

GANP Regulates the Choice of DNA Repair Pathway by DNA-PKcs Interaction in AID-Dependent IgV Region Diversification

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