The response to DNA damage during differentiation: Pathways and consequences

Fortini, Paola; Ferretti, C; Dogliotti, Eugenia

doi:10.1016/j.mrfmmm.2013.03.004

Cited by 45 publications

(38 citation statements)

References 104 publications

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“…Another feature that distinguishes undifferentiated ESCs from differentiating ESCs is the choice of DNA damage repair pathways. ESCs remove ionising-radiation-induced DNA damage through homologous recombination rather than by error-prone non-homologous end joining (NHEJ) (Fortini et al, 2013). To our knowledge, no detailed experimental data on the DNA repair mechanism during ESC differentiation are available.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of KDM6 activity during murine ES cell differentiation induces DNA damage

Hofstetter

Kampka

Huppertz

et al. 2016

Journal of Cell Science

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Pluripotent embryonic stem cells (ESCs) are characterised by their capacity to self-renew indefinitely while maintaining the potential to differentiate into all cell types of an adult organism. Both the undifferentiated and differentiated states are defined by specific gene expression programs that are regulated at the chromatin level. Here, we have analysed the contribution of the H3K27me2-and H3K27me23-specific demethylases KDM6A and KDM6B to murine ESC differentiation by employing the GSK-J4 inhibitor, which is specific for KDM6 proteins, and by targeted gene knockout (KO) and knockdown. We observe that inhibition of the H3K27 demethylase activity induces DNA damage along with activation of the DNA damage response (DDR) and cell death in differentiating but not in undifferentiated ESCs. Laser microirradiation experiments revealed that the H3K27me3 mark, but not the KDM6B protein, colocalise with γH2AX-positive sites of DNA damage in differentiating ESCs. Lack of H3K27me3 attenuates the GSK-J4-induced DDR in differentiating Eed-KO ESCs. Collectively, our findings indicate that differentiating ESCs depend on KDM6 and that the H3K27me3 demethylase activity is crucially involved in DDR and survival of differentiating ESCs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of KDM6 activity during murine ES cell differentiation induces DNA damage

Hofstetter

Kampka

Huppertz

et al. 2016

Journal of Cell Science

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“…Among primary liver cancers, hepatocellular carcinoma (HCC), the major histological subtype, is associated with multiple risk factors, including hepatitis B and C virus (HBV and HCV) infection, alcohol consumption, obesity, and diet contamination (Figure 1). HCC frequently arises in the context of chronic injury and inflammation that promote DNA damage and chromosomal aberrations [3], which trigger a prompt set of signaling events known as the DNA damage response (DDR) pathways which coordinate DNA repair, cell cycle arrest, and ultimately cell death or senescence [4–6]. There are several types of DNA damage and corresponding repair mechanisms that have been implicated in HCC such as stalled DNA replication fork by homologous recombination (HR) [7], base mismatches by mismatch repair (MMR) [8], and the most serious form of DNA damage, double-strand break (DSB) [9], by nonhomologous end joining (NHEJ) [10, 11] (Figure 1).…”

Section: The Common Causes Of Genetic Alterations and Genomic Instmentioning

confidence: 99%

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

Yang

Chang

Wei

et al. 2014

BioMed Research International

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Hepatocellular carcinoma (HCC) has been known as one of the most lethal human malignancies, due to the difficulty of early detection, chemoresistance, and radioresistance, and is characterized by active angiogenesis and metastasis, which account for rapid recurrence and poor survival. Its development has been closely associated with multiple risk factors, including hepatitis B and C virus infection, alcohol consumption, obesity, and diet contamination. Genetic alterations and genomic instability, probably resulted from unrepaired DNA lesions, are increasingly recognized as a common feature of human HCC. Dysregulation of DNA damage repair and signaling to cell cycle checkpoints, known as the DNA damage response (DDR), is associated with a predisposition to cancer and affects responses to DNA-damaging anticancer therapy. It has been demonstrated that various HCC-associated risk factors are able to promote DNA damages, formation of DNA adducts, and chromosomal aberrations. Hence, alterations in the DDR pathways may accumulate these lesions to trigger hepatocarcinogenesis and also to facilitate advanced HCC progression. This review collects some of the most known information about the link between HCC-associated risk factors and DDR pathways in HCC. Hopefully, the review will remind the researchers and clinicians of further characterizing and validating the roles of these DDR pathways in HCC.

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“…Proliferation competent cells can enter cell-cycle arrest and repair DNA damage; alternatively cells can activate cell death pathways (4). However, cell decision-making in the DDR is influenced by cell cycle status (5). Much less is known about the intrinsic properties of DDR and DNA repair in postmitotic, terminally differentiated cells such as neurons and multinucleated myofibers in skeletal muscle (6)(7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

Fayzullina

Martin

2016

J Neuropathol Exp Neurol

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We studied DNA damage response (DDR) and DNA repair capacities of skeletal muscle cells from a mouse model of infantile spinal muscular atrophy (SMA) caused by loss-of-function mutation of survival of motor neuron (Smn). Primary myocyte cultures derived from skeletal muscle satellite cells of neonatal control and mutant SMN mice had similar myotube length, myonuclei, satellite cell marker Pax7 and differentiated myotube marker myosin, and acetylcholine receptor clustering. DNA damage was induced in differentiated skeletal myotubes by c-irradiation, etoposide, and methyl methanesulfonate (MMS). Unexposed control and SMA myotubes had stable genome integrity. After c-irradiation and etoposide, myotubes repaired most DNA damage equally. Control and mutant myotubes exposed to MMS exhibited equivalent DNA damage without repair. Control and SMA myotube nuclei contained DDR proteins phosphop53 and phospho-H2AX foci that, with DNA damage, dispersed and then re-formed similarly after recovery. We conclude that mouse primary satellite cell-derived myotubes effectively respond to and repair DNA strand-breaks, while DNA alkylation repair is underrepresented. Morphological differentiation, genome stability, genome sensor, and DNA strand-break repair potential are preserved in mouse SMA myocytes; thus, reduced SMN does not interfere with myocyte differentiation, genome integrity, and DNA repair, and faulty DNA repair is unlikely pathogenic in SMA.

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The response to DNA damage during differentiation: Pathways and consequences

Cited by 45 publications

References 104 publications

Inhibition of KDM6 activity during murine ES cell differentiation induces DNA damage

Inhibition of KDM6 activity during murine ES cell differentiation induces DNA damage

Involvement of DNA Damage Response Pathways in Hepatocellular Carcinoma

DNA Damage Response and DNA Repair in Skeletal Myocytes From a Mouse Model of Spinal Muscular Atrophy

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