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

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

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 Quiescent Hematopoietic Stem Cells Accumulate DNA Damage during Aging that Is Repaired upon Entry into Cell Cycle

2014 ◽  
Vol 15 (1) ◽  
pp. 37-50 ◽  
Author(s):  
Isabel Beerman ◽  
Jun Seita ◽  
Matthew A. Inlay ◽  
Irving L. Weissman ◽  
Derrick J. Rossi
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem

Deregulated Gene Expression Pathways in Myelodysplastic Syndrome Hematopoietic Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 735-735 ◽  
Author(s):  
Andrea Pellagatti ◽  
Mario Cazzola ◽  
Aristoteles Giagounidis ◽  
Janet Perry ◽  
Luca Malcovati ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Stem Cells ◽  
Dna Damage ◽  
Gene Ontology ◽  
Hematopoietic Stem Cells ◽  
Molecular Pathogenesis ◽  
Beta Catenin ◽  
Trisomy 8 ◽  
Hematopoietic Stem

Abstract Abstract 735 The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies that are characterized by ineffective hematopoiesis resulting in peripheral cytopenias and a hypercellular bone marrow. In order to gain insight into the molecular pathogenesis of the MDS, we have determined the transcriptome of the hematopoietic stem cells (HSC) of 183 MDS patients and 17 healthy controls. The CD34+ cells obtained from MDS patients and healthy individuals were analyzed using Affymetrix U133 Plus2.0 arrays. Global pathway analysis using the Ingenuity software and the DAVID database has identified critical deregulated gene pathways and gene ontology (functional) groups perturbed in MDS HSC compared with normal HSC. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathway. Moreover, we have identified multiple pathways that are deregulated in specific MDS karyotypic groups and between early (subtype RA) and advanced MDS (subtype RAEB2). Among the most significantly deregulated gene pathways and ontology groups in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of the cell cycle, DNA damage response and checkpoint pathways. The clinical behavior of patients with del(5q), +8 or–7/del(7q) is different and we have identified distinct gene expression profiles and deregulated gene pathways for MDS defined by these major karyotypic groups. The most significantly deregulated gene pathways in del(5q) MDS include primary immunodeficiency signaling, Wnt/beta-catenin signaling, integrin signaling, cell cycle regulation and Huntington's disease signaling. Patients with the 5q- syndrome also show deregulation of the p53 pathway. Moreover, chromatin assembly and translation are among the most significant gene ontology groups in del(5q) MDS. We have found that MDS with the–7/del(7q) is characterized by deregulation of multiple pathways involved in cell survival, differentiation, apoptosis and growth, and include SAPK/JNK, NF-kB, PI3K/AKT and ceramide signaling pathways. Strikingly, all of the most significantly deregulated gene pathways in trisomy 8 MDS in our study concern or are associated with the immune response, and include B-cell receptor signaling, antigen presentation and CTLA4 signaling in Cytotoxic T lymphocytes pathways. These data are consistent with an immune system role in the pathogenesis of MDS with trisomy 8. Importantly, much of the deregulated pathway data generated in this study is in accord with the known biology of MDS. On the basis of our observations, we suggest a model for MDS in which immune deregulation and activation of apoptosis pathways in early MDS cells, consistent with clinically observed ineffective hematopoiesis, functions as a barrier to prevent leukemic transformation. Disruption of the DNA damage check points in advanced MDS results in an increase in the error rate of DNA repair with a concomitant increase in genomic instability, leading to evolution to AML. This is the first study to determine deregulated gene pathways and ontology groups in the HSC compartment of a large group of patients with MDS. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype, provide important new insights into the molecular pathogenesis of this disorder, and may represent new targets for therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

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