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1 year ago

Insights On How Doxorubicin
Helped Me To Get Famous And Rich

Highly regenerative formerly tissues this kind of as blood will have to possess effective DNA harm responses (DDR) that stability long-term regeneration with safety from leukemogenesis. Hematopoietic stem cells (HSCs) sustain life-long blood production, nonetheless their response to E3 Ligase DNA damage stays largely unexplored. We report that human HSCs exhibit delayed DNA double-strand break rejoining, persistent gamma H2AX foci, and enhanced p53- and ASPP1-dependent apoptosis right after gamma-radiation when compared to progenitors. p53 inactivation or Bcl-2 overexpression decreased radiation-induced apoptosis and preserved in vivo repopulating HSC function. Despite very similar protection from irradiation-induced apoptosis, only Bcl-2-overexpressing HSCs showed higher self-renewal capability, establishing that intact p53 positively regulates self-renewal independently from apoptosis. The reduced self-renewal of HSCs with inactivated p53 was related with increased spontaneous gamma H2AX foci in secondary transplants of HSCs. Our data reveal distinct physiological roles of p53 that collectively assure optimal HSC function: apoptosis regulation and prevention of gamma H2AX foci accumulation on HSC self-renewal.

1 year ago

The Way In Which E3 Ligase
Made Me Rich And Famous

Most adult stem cells, such as hematopoieticphase 3 stem cells (HSCs), are maintained within a quiescent or resting state in vivo. Quiescence is broadly thought of for being an important E3 Ligase protective mechanism for stem cells that minimizes endogenous tension induced by cellular respiration and DNA replication. We demonstrate that HSC quiescence may also have detrimental results. We observed that HSCs have unique cell-intrinsic mechanisms making certain their survival in response to ionizing irradiation (IR), which include enhanced prosurvival gene expression and solid activation of p53-mediated DNA harm response. We demonstrate that quiescent and proliferating HSCs are equally radioprotected but use various kinds of DNA restore mechanisms. We describe how nonhomologous finish joining (NHEJ)-mediated DNA repair in quiescent HSCs is associated with acquisition of genomic rearrangements, which can persist in vivo and contribute to hematopoietic abnormalities. Our benefits demonstrate that quiescence is actually a double-edged sword that renders HSCs intrinsically vulnerable to mutagenesis following DNA damage.