Myocardial Oxygen Supply under Critical Conditions, the Effects of Hemodilution and Fluorocarbons

Fennema, M.; Erdmann, W.; Faithfull, N. S.

doi:10.1007/978-1-4615-3428-0_63

Cited by 1 publication

(1 citation statement)

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“…Particularly, inducible expression of p53 carrying the TAD1 mutation resulted in cell death without significant cell cycle arrest (36), whereas p53-TAD2 mutants were unable to induce apoptosis but retain a modest ability to undergo cell cycle arrest (35). Similarly, an apoptotic defect was also found in a mouse with deletion of p53 proline-rich residues (9). p53 plays a prominent role as a facilitator of DNA repair by halting the cell cycle to allow time for the repair machineries to restore genome stability.…”

Section: Introductionmentioning

confidence: 98%

Transactivation domain of p53 regulates DNA repair and integrity in human iPS cells

Kannappan

Mattapally

Wagle

et al. 2018

American Journal of Physiology-Heart and Circulatory Physiology

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The role of p53 transactivation domain (p53-TAD), a multifunctional and dynamic domain, on DNA repair and retaining DNA integrity in human induced pluripotent stem cells (hiPSCs) has never been studied. p53-TAD was knocked out in iPSCs using CRISPR/Cas9 and was confirmed by DNA sequencing. p53-TAD knockout (KO) cells were characterized by accelerated proliferation, decreased population doubling time, and unaltered Bcl-2, Bcl-2-binding component 3, insulin-like growth factor 1 receptor, and Bax and altered Mdm2, p21, and p53-induced death domain transcript expression. In p53-TAD KO cells, the p53-regulated DNA repair proteins xeroderma pigmentosum group A, DNA polymerase H, and DNA-binding protein 2 expression were found to be reduced compared with p53 wild-type cells. Exposure to a low dose of doxorubicin (Doxo) induced similar DNA damage and DNA damage response (DDR) as measured by RAD50 and MRE11 expression, checkpoint kinase 2 activation, and γH2A.X recruitment at DNA strand breaks in both cell groups, indicating that silence of p53-TAD does not affect the DDR mechanism upstream of p53. After removal of Doxo, p53 wild-type hiPSCs underwent DNA repair, corrected their damaged DNA, and restored DNA integrity. Conversely, p53-TAD KO hiPSCs did not undergo complete DNA repair and failed to restore DNA integrity. More importantly, continuous culture of p53-TAD KO hiPSCs underwent G/M cell cycle arrest and expressed the cellular senescent marker p16. Our data clearly show that silence of the TAD of p53 did not affect DDR but affected the DNA repair process, implying the crucial role of p53-TAD in maintaining DNA integrity. Therefore, activating p53-TAD domain using small molecules may promote DNA repair and integrity of cells and prevent cellular senescence.

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Section: Introductionmentioning

confidence: 98%