Akt1 Stimulates Homologous Recombination Repair of DNA Double-Strand Breaks in a Rad51-Dependent Manner

Mueck, Katharina; Rebholz, Simone; Harati, Mozhgan Dehghan; Rodemann, H. Peter; Toulany, Mahmoud

doi:10.3390/ijms18112473

Cited by 36 publications

(40 citation statements)

References 77 publications

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“…3C). RAD51 is a critical factor in HR repair (29,30). We detected RAD51 in ionizing radiation-induced foci in 293T cells ( Fig.…”

Section: Rsv Promotes Dna Damage Repair Through the Homologous Recombmentioning

confidence: 78%

Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Gao

et al. 2019

FASEB j.

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Resveratrol (RSV) has broad prospective applications as a radiation protection drug, but its mechanism of action is not yet clear. Here, we found that 5 µM RSV can effectively reduce the cell death caused by irradiation. Irradiation leads to G2/M phase arrest in the cell cycle, whereas RSV treatment increases S‐phase cell cycle arrest, which is associated with sirtuin 1 (SIRT1) regulation. Meanwhile, RSV promotes DNA damage repair, mainly by accelerating the efficiency of homologous recombination repair. Under oxidative stress, tyrosyl‐tRNA synthetase (TyrRS) is transported to the nucleus to protect against DNA damage. RSV can promote TyrRS acetylation, thus promoting TyrRS to enter the nucleus, where it regulates the relevant signaling proteins and reduces apoptosis and DNA damage. SIRT1 is a deacetylase, and SIRT1 knockdown or inhibition can increase TyrRS acetylation levels, further reducing radiation‐induced apoptosis after RSV treatment. Our study revealed a new radiation protection mechanism for RSV, in which the acetylation of TyrRS and its translocation into the nucleus is promoted, and this mechanism may also represent a novel protective target against irradiation.—Gao, P., Li, N., Ji, K., Wang, Y., Xu, C., Liu, Y., Wang, Q., Wang, J., He, N., Sun, Z., Du, L., Liu, Q. Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage. FASEB J. 33, 8083–8093 (2019). http://www.fasebj.org

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“…3C). RAD51 is a critical factor in HR repair (29,30). We detected RAD51 in ionizing radiation-induced foci in 293T cells ( Fig.…”

Section: Rsv Promotes Dna Damage Repair Through the Homologous Recombmentioning

confidence: 78%

Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Gao

et al. 2019

FASEB j.

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“…Accumulating evidence indicates a regulatory role of Akt isoforms-especially Akt1 and Akt3 in NHEJ [12][13][14][15]. Akt1 has also been reported to be potentially involved in HR-dependent repair processes [16], however these data conflict with other reports [16][17][18].…”

Section: Introductionmentioning

confidence: 86%

“…Mueck et al [16] indicated that Akt1 promotes HRR by influencing Rad51 protein levels and foci formation. Jia et al [17] reported a negative role of Akt on HRR via the CHK1-Rad51 pathway in BRCA1-deficient cells.…”

Section: Introductionmentioning

confidence: 99%

“…Likewise, Plo et al [18] postulated that Akt1 inhibits homologous recombination by inducing cytoplasmic retention of BRCA1 and RAD51 as detected with immuno-fluorescence. Thus, the current functional role of Akt and its isoforms in HR is not clearly understood and the existing data are conflicting [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…This work is based on knock-down and knock-out strategies-we more specifically characterized the importance of Akt isoforms Akt1 and Akt2 for homologous recombination repair of DSBs in human colorectal cancer cells in vitro. In contrast to Mueck et al [16], Jia et al [17], and Plo et al [18], the HR analyses were performed primarily in cells positive for the centromeric protein CENP-F. This is a clear indicator of the late S-as well as G2-phase cells.…”

Section: Introductionmentioning

confidence: 99%

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Depletion of Akt1 and Akt2 Impairs the Repair of Radiation-Induced DNA Double Strand Breaks via Homologous Recombination

Gol

Rodemann

Dittmann

2019

IJMS

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Homologous recombination repair (HRR), non-homologous end-joining (NHEJ) and alternative NHEJ are major pathways that are utilized by cells for processing DNA double strand breaks (DNA-DSBs); their function plays an important role in the radiation resistance of tumor cells. Conflicting data exist regarding the role of Akt in homologous recombination (HR), i.e., the regulation of Rad51 as a major protein of this pathway. This study was designed to investigate the specific involvement of Akt isoforms in HRR. HCT116 colon cancer cells with stable AKT-knock-out and siRNA-mediated AKT-knockdown phenotypes were used to investigate the role of Akt1 and Akt2 isoforms in HR. The results clearly demonstrated that HCT116 AKT1-KO and AKT2-KO cells have a significantly reduced Rad51 foci formation 6 h post irradiation versus parental cells. Depletion of Akt1 and Akt2 protein levels as well as inhibition of Akt kinase activity resulted in an increased number of residual-γH2AX in CENP-F positive cells mainly representing the S and G2 phase cells. Furthermore, inhibition of NHEJ and HR using DNA-PK and Rad51 antagonists resulted in stronger radiosensitivity of AKT1 and AKT2 knockout cells versus wild type cells. These data collectively show that both Akt1 and Akt2 are involved in DSBs repair through HRR.

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Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

Yedla,

Bhamidipati,

Syed

et al. 2024

Cell Biochemistry & Function

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The interaction between murine double minute 2 (MDM2) and p53, marked by transcriptional induction and feedback inhibition, orchestrates a functional loop dictating cellular fate. The functional loop comprising p53‐MDM2 axis is made up of an interactome consisting of approximately 81 proteins, which are spatio‐temporally regulated and involved in DNA repair mechanisms. Biochemical and genetic alterations of the interactome result in dysregulation of the p53‐mdm2 axis that leads to gastrointestinal (GI) cancers. A large subset of interactome is well known and it consists of proteins that either stabilize p53 or MDM2 and proteins that target the p53‐MDM2 complex for ubiquitin‐mediated destruction. Upstream signaling events brought about by growth factors and chemical messengers invoke a wide variety of posttranslational modifications in p53‐MDM2 axis. Biochemical changes in the transactivation domain of p53 impact the energy landscape, induce conformational switching, alter interaction potential and could change solubility of p53 to redefine its co‐localization, translocation and activity. A diverse set of chemical compounds mimic physiological effectors and simulate biochemical modifications of the p53‐MDM2 interactome. p53‐MDM2 interactome plays a crucial role in DNA damage and repair process. Genetic aberrations in the interactome, have resulted in cancers of GI tract (pancreas, liver, colorectal, gastric, biliary, and esophageal). We present in this article a review of the overall changes in the p53‐MDM2 interactors and the effectors that form an epicenter for the development of next‐generation molecules for understanding and targeting GI cancers.

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Akt1 Stimulates Homologous Recombination Repair of DNA Double-Strand Breaks in a Rad51-Dependent Manner

Cited by 36 publications

References 77 publications

Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Resveratrol targets TyrRS acetylation to protect against radiation‐induced damage

Depletion of Akt1 and Akt2 Impairs the Repair of Radiation-Induced DNA Double Strand Breaks via Homologous Recombination

Working title: Molecular involvement of p53‐MDM2 interactome in gastrointestinal cancers

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