Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest

Yun, Jeanho; Zhong, Qing; Kwak, Jong Young; Lee, Wen‐Hwa

doi:10.1038/sj.onc.1208575

Cited by 44 publications

(37 citation statements)

References 41 publications

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“…Bromodeoxyuridine (BrdUrd) was added for the last hour. Cells were then harvested and DNA was stained with anti-BrdUrd monocolonal antibody (mAb; Santa Cruz) and propidium iodide, and analyzed by flow cytometry as described elsewhere (12).…”

Section: Cell-cycle Analysismentioning

confidence: 99%

HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression

Izawa

Sato

et al. 2011

Cancer Research

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DNA replication, recombination, and repair are highly interconnected processes the disruption of which must be coordinated in cancer. HERC2, a large HECT protein required for homologous recombination repair, is an E3 ubiquitin ligase that targets breast cancer suppressor BRCA1 for degradation. Here, we show that HERC2 is a component of the DNA replication fork complex that plays a critical role in DNA elongation and origin firing. In the presence of BRCA1, endogenous HERC2 interacts with Claspin, a protein essential for G 2 -M checkpoint activation and replication fork stability. Claspin depletion slowed S-phase progression and additional HERC2 depletion reduced the effect of Claspin depletion. In addition, HERC2 interacts with replication fork complex proteins. Depletion of HERC2 alleviated the slow replication fork progression in Claspin-deficient cells, suppressed enhanced origin firing, and led to a decrease in MCM2 phosphorylation. In a HERC2-dependent manner, treatment of cells with replication inhibitor aphidicolin enhanced MCM2 phosphorylation. Taken together, our results suggest that HERC2 regulates DNA replication progression and origin firing by facilitating MCM2 phosphorylation. These findings establish HERC2 as a critical function in DNA repair, checkpoint activation, and DNA replication. Cancer Res; 71(17); 5621-5. Ó2011 AACR.

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Section: Cell-cycle Analysismentioning

confidence: 99%

HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression

Izawa

Sato

et al. 2011

Cancer Research

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“…To measure cell survival after genotoxic stress, a clonogenic survival assay was performed as described previously (Yun et al, 2005). Cells (1 Â 10 3 ) were seeded into a 100 mm dish and exposed to the indicated dose of IR or UV.…”

Section: Clonogenic Survival Assaymentioning

confidence: 99%

Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation

Kim

et al. 2009

Oncogene

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The serine/threonine protein kinase, Akt/PKB, has an essential function in cell survival during response to various stresses. Recent studies have demonstrated that Akt isoforms exhibit some distinct physiological functions, but the isotype-specific functions for Akt in the stress response have not been fully identified. In this study, we analysed the cellular response to genotoxic stress using isogenic wild-type, Akt1À/À and Akt2 À/À mouse embryonic fibroblasts (MEFs). Marked hypersensitivity of Akt2MEFs was observed to UV irradiation, whereas wild-type and Akt1À/À MEFs showed comparable levels of resistance. Akt2À/À mouse aortic endothelial cells also showed hypersensitivity to UV and the reconstitution of Akt2 expression in the Akt2 À/À MEFs restored the UV resistance of the cells. Interestingly, upon UV irradiation, JNK and p38 were significantly upregulated in Akt2MEFs, compared to wild-type and Akt1 À/À MEFs. Additionally, inhibition of JNK and p38 activation reduced UV-induced cell death. Furthermore, both the hyperactivation of JNK and p38 and the UV-induced cell death in Akt2 À/À MEFs were completely inhibited by restoring Akt2 expression. These results indicate that Akt2, but not Akt1, is essential for cell survival upon UV irradiation, and that Akt2 prevents UV-induced cell death by inhibiting activation of JNK and p38.

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“…BRCA1 also functions in DSB repair by HR. [8][9][10][11][12][13][14][15][16] Interestingly, unlike BRCA2, BRCA1 also functions in the alternative non-homologous end-joining (NHEJ) pathway. [17][18][19][20][21] BRCA1 functions in many other cellular processes including transcription coupled repair, 22,23 chromatin remodelling, 24,25 XIST-dependent X-chromosome silencing, 26 DNA damage signalling 17,27 and transcription elongation.…”

Section: Introductionmentioning

confidence: 99%

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

Durant¹,

Nickoloff²

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=2027 KEY WORDSBRCA1, NHEJ, HR, MRE11, RAD50, NBS1, exonuclease, cell cycle, DSB repair ABBREVIATIONS NHEJ non-homologous end-joining HR homologous recombination DSB double-strand break ACKNOWLEDGEMENTSOur research on the NHEJ/HR interface is supported by grant CA100862 from the National Cancer Institute, NIH. ReviewGood Timing in the Cell Cycle for Precise DNA Repair by BRCA1 ABSTRACTIt is now clear that large DNA-binding proteins have evolved in mammals to orchestrate the relatively ancient process of DNA recombinational repair. These proteins are recruited to accurately repair DNA double strand breaks (DSBs)-the frequent, potentially lethal and mutagenic lesions in the genomes of all organisms. An essential mammalian regulator of DSB repair is BRCA1. Heterozygous BRCA1 mutations predispose individuals to breast, ovarian and other secondary cancers. BRCA1-defective cells exhibit reduced DSB repair, sensitivity to a wide range of DNA damaging agents, genomic instability and defects in the S-phase checkpoint, transcription and chromatin remodelling. DSBs can be repaired by RAD51/RPA-dependent homologous recombination (HR) or DNA-PK-dependent nonhomologous end-joining (NHEJ). Both of these pathways can be imprecise and mutagenic. BRCA1 plays a central role in promoting accurate repair by both HR and NHEJ. Consistent with recent evidence, we have assembled a novel cell-cycle-dependent model in which DNA-PK inhibits RPA in S-phase of the cell cycle, while BRCA1 inhibits the exonuclease processivity of the MRE11/RAD50/NBS1 (MRN) complex and facilitates the removal of RPA in S and G 2 phase. This model provides an explanation for how BRCA1 promotes accurate DSB repair during various phases of the cell cycle and also accounts for the dual effects that BRCA1 and MRN activity have upon DNA repair and S-phase arrest.

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Hypersensitivity of Brca1-deficient MEF to the DNA interstrand crosslinking agent mitomycin C is associated with defect in homologous recombination repair and aberrant S-phase arrest

Cited by 44 publications

References 41 publications

HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression

HERC2 Interacts with Claspin and Regulates DNA Origin Firing and Replication Fork Progression

Akt2, but not Akt1, is required for cell survival by inhibiting activation of JNK and p38 after UV irradiation

Good Timing in the Cell Cycle for Precise DNA Repair by BRCA1

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