scholarly journals Terminal differentiation induction as DNA damage response in hematopoietic stem cells by GADD45A

2016 ◽  
Vol 44 (7) ◽  
pp. 561-566 ◽  
Author(s):  
Susanne Wingert ◽  
Michael A. Rieger
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Terminal Differentiation ◽  
Hematopoietic Stem ◽  
Differentiation Induction ◽  
Damage Response

scholarly journals Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells

2014 ◽  
Vol 206 (4) ◽  
pp. 2064OIA143
Author(s):  
Cesare Lancini ◽  
Paul C.M. van den Berk ◽  
Joseph H.A. Vissers ◽  
Gaetano Gargiulo ◽  
Ji-Ying Song ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Hematopoietic Stem ◽  
Functional Integrity ◽  
Damage Response

scholarly journals DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival

Stem Cells ◽  
2016 ◽  
Vol 34 (3) ◽  
pp. 699-710 ◽  
Author(s):  
Susanne Wingert ◽  
Frederic B. Thalheimer ◽  
Nadine Haetscher ◽  
Maike Rehage ◽  
Timm Schroeder ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Response Gene ◽  
Hematopoietic Stem ◽  
Damage Response

Distinct Roles of CHK2 and Cell Death in Suppressing Oncogenic Potential of Tandem DNA Breaks in Human Hematopoietic Stem Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2659-2659
Author(s):  
Shahar Biechonski ◽  
Muhammad Yassin ◽  
Nasma Aqaqe ◽  
Leonid Olender ◽  
Melanie Rall ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cell Death ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Parp Cleavage ◽  
Hematopoietic Stem ◽  
Damage Response ◽  
Induced Apoptosis ◽  
Dna Ends

Abstract DNA double strand breaks (DSBs) are the most dangerous genomic lesions that can be induced by endogenous and exogenous sources. DNA damage response determines cellular fate decisions following DSBs and can lead to cell death or cell survival. Incorrect DSB repair via canonical Non-Homologous End Joining (cNHEJ) or Alternative NHEJ (Alt-NHEJ) is the main source of oncogenic aberrations, including leukemogenic translocations, DNA sequence deletions and insertions. The long life span of Hematopoietic Stem Cells (HSC) and their practically unlimited potential for self-renewal requires efficient strategies to cope with DNA damage to eliminate erroneous genetic information inheritance to daughter cells. Although the critical importance of maintaining genome integrity for normal hematopoiesis and prevention of leukemogenesis has been established, definitive analysis of DNA damage response and its mutagenic outcomes in human HSC and Progenitors in response to DSBs is missing. Here we repot that human cord blood purified HSC (defined as CD34+CD38-CD45RA-) are exquisitely sensitive to irradiation (IR)-induced apoptosis in contrast to committed progenitors (defined as CD34+CD38+) as validated by PARP cleavage induction. Interestingly, pan-caspase inhibitor Z-VAD-FMK prevented, whereas CHK2 inhibitor (PV1019) failed in altering apoptosis onset of irradiated HSC. Strikingly, CHK2 inhibitor blocked IR-induced apoptosis in cycling HSC, suggesting differential wiring of DNA damage induced apoptosis in quiescent versus mitogenically stimulated HSC. To characterize cNHEJ repair pathway and its mutagenic potential in live primitive hematopoietic cells we analyzed I-SceI endonuclease induced tandem DSBs joining capacity using DNA repair reporter assay. We found that HSC exhibit inferior cNHEJ capacity as compared with committed progenitors. By decreasing DSBs persistence we revealed that progenitors utilize to the higher degree than HSC the mutagenic component of cNHEJ pathway that results in DNA deletions. We identified HSC-specific contribution of CHK2 kinase activity in limiting incorrect DNA ends joining. Blockade of apoptosis induction also led to the selective increase in mutagenic NHEJ in HSC. On the other hand, inhibition of DNA-PK led to increased oncogenic repair in progenitors only. Importantly, we revealed that HSC utilized mutagenic Alt-NHEJ pathway that depends on microhomologies search and extensive DNA ends processing less efficiently than Progenitors. Thus, our results indicate that oncogenic consequences of DSBs repair in HSC are distinctly minimized by the non-redundant cell death and CHK2 dependent mechanisms. More broadly, these findings will help to elucidate additional repair modifiers and the mechanism by which HSC contend with genotoxic stress. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Distinctive DNA Damage Response in Human Hematopoietic Stem Cells Reveals an Apoptosis-Independent Role for p53 in Self-Renewal

2010 ◽  
Vol 7 (2) ◽  
pp. 186-197 ◽  
Author(s):  
Michael Milyavsky ◽  
Olga I. Gan ◽  
Magan Trottier ◽  
Martin Komosa ◽  
Ofer Tabach ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Dna Damage Response ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Damage Response

scholarly journals Characterizing the DNA damage response in putative stem cells of resected normal lung and matched NSCLC patient samples

2017 ◽  
Vol 28 ◽  
pp. ii4
Author(s):  
T.M. Marti ◽  
C.C. Tièche ◽  
R. Peng ◽  
S.R.R. Hall ◽  
L. Froment ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Nsclc Patient ◽  
Normal Lung ◽  
Damage Response
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