MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy

Brown, Kristin K.; Montaser‐Kouhsari, Laleh; Beck, Andrew H.; Toker, Alex

doi:10.1016/j.celrep.2015.05.004

Cited by 44 publications

(57 citation statements)

References 31 publications

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“…Cell viability was assessed using sulforhodamine B assay as previously described (18). Briefly, adherent cells were fixed with 12.5% (w/v) trichloroacetic acid for 1 hour at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling

et al. 2017

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Despite the high incidence of oncogenic mutations in PIK3CA, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (PI3K), PI3K inhibitors have yielded little clinical benefit for breast cancer patients. Recent epidemiological studies have suggested a therapeutic benefit from aspirin intake in cancers harboring oncogenic PIK3CA. Here we show that mutant PIK3CA-expressing breast cancer cells have greater sensitivity to aspirin-mediated growth suppression than their wild-type counterparts. Aspirin decreased viability and anchorage-independent growth of mutant PIK3CA breast cancer cells independently of its effects on cyclooxygenase-2 (COX-2) and nuclear factor-kappa B (NF-κB). We ascribed the effects of aspirin to AMP-activated protein kinase (AMPK) activation, mammalian target of rapamycin complex 1 (mTORC1) inhibition, and autophagy induction. In vivo, oncogenic PIK3CA-driven mouse mammary tumors treated daily with aspirin resulted in decreased tumor growth kinetics, while combination therapy of aspirin and a PI3K inhibitor further attenuated tumor growth. Our study supports evaluation of aspirin and PI3K pathway inhibitors as combination therapy for targeting breast cancer.

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“…Cell viability was assessed using sulforhodamine B assay as previously described (18). Briefly, adherent cells were fixed with 12.5% (w/v) trichloroacetic acid for 1 hour at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling

et al. 2017

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“…These included, for example, XLF (XRCC4-like factor) and UBE2S (ubiquitin-conjugating enzyme E2 S) as Akt target proteins connected to NHEJ, as well as MERIT40 (mediator of Rap80 Interactions and Targeting 40 kDa), and EMSY (BRCA2-interacting transcriptional repressor) with suggested functions in HRR [9,10,11,14,15]; reviewed by Reference [5]. …”

Section: Introductionmentioning

confidence: 99%

Restraining Akt1 Phosphorylation Attenuates the Repair of Radiation-Induced DNA Double-Strand Breaks and Reduces the Survival of Irradiated Cancer Cells

Szymonowicz

Oeck

Krysztofiak

et al. 2018

IJMS

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The survival kinase protein kinase B (Akt) participates in the regulation of essential subcellular processes, e.g., proliferation, growth, survival, and apoptosis, and has a documented role in promoting resistance against genotoxic stress including radiotherapy, presumably by influencing the DNA damage response and DNA double-strand break (DSB) repair. However, its exact role in DSB repair requires further elucidation. We used a genetic approach to explore the consequences of impaired phosphorylation of Akt1 at one or both of its key phosphorylation sites, Threonine 308 (T308) or Serine 473 (S473), on DSB repair and radiosensitivity to killing. Therefore, we overexpressed either the respective single or the double phosphorylation-deficient mutants (Akt1-T308A, Akt1-S473A, or Akt1-T308A/S473A) in TRAMPC1 murine prostate cancer cells (TrC1) and measured the DSB repair kinetics and clonogenic cell survival upon irradiation. Only the expression of the Akt1-T308A/S473A induced a significant delay in the kinetics of DSB repair in irradiated TrC1 as determined by the γH2A.X (H2A histone family, member X) assay and the neutral comet assay, respectively. Moreover, Akt1-T308A/S473A-expressing cells were characterized by increased radiosensitivity compared to Akt1-WT (wild type)-expressing cells in long-term colony formation assays. Our data reveal that Akt1’s activation state is important for the cellular radiation response, presumably by modulating the phosphorylation of effector proteins involved in the regulation of DSB repair.

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“…Jiang and colleagues [78] demonstrated that end resection and HR are reduced after ICLs damage in MERIT40-null cells. Another study suggested that MERIT40 might be a drug target because MERIT40 was phosphorylated by Akt, which is activated by cancer drug doxorubicin [80]. Phosphorylated MERIT40 increases the accumulation of BRCA1-A complex at sites of DNA damage induced by doxorubicin, which is a cytotoxic chemotherapy drug.…”

Section: Merit40mentioning

confidence: 99%

Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

Her

Lee

Kim

et al. 2016

ABBS

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Sustaining genomic integrity is essential for preventing onset of cancers. Therefore, human cells evolve to have refined biological pathways to defend genetic materials from various genomic insults. DNA damage response and DNA repair pathways essential for genome maintenance are accomplished by cooperative executions of multiple factors including breast cancer type 1 susceptibility protein (BRCA1). BRCA1 is initially identified as an altered gene in the hereditary breast cancer patients. Since then, tremendous efforts to understand the functions of BRAC1 reveal that BRCA1 is found in distinct complexes, including BRCA1-A, BRCA1-B, BRCA1-C, and the BRCA1/ PALB2/BRCA2 complex, and plays diverse roles in a context-dependent manner. Among the complexes, BRCA1-A is critical for BRCA1 recruitment to the sites of DNA damage. Factors comprising the BRCA1-A include RAP80, CCDC98/Abraxas, BRCC36, BRCC45, BARD1, BRCA1, and MERIT40, a RAP80-associated factor. In this review, we summarize recent findings of the factors that form the BRCA1-A complex.

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MERIT40 Is an Akt Substrate that Promotes Resolution of DNA Damage Induced by Chemotherapy

Cited by 44 publications

References 31 publications

Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling

Aspirin Suppresses Growth in PI3K-Mutant Breast Cancer by Activating AMPK and Inhibiting mTORC1 Signaling

Restraining Akt1 Phosphorylation Attenuates the Repair of Radiation-Induced DNA Double-Strand Breaks and Reduces the Survival of Irradiated Cancer Cells

Factors forming the BRCA1-A complex orchestrate BRCA1 recruitment to the sites of DNA damage

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