Differentiation of Human Induced Pluripotent or Embryonic Stem Cells Decreases the DNA Damage Repair by Homologous Recombination
| Autor: | Clayton R. Hunt, Anjana Tiwari, Vijay Charaka, Alexander Y. Kots, Kalpana Mujoo, Nobuo Horikoshi, Dharmendra Kumar Singh, Sharmistha Chakraborty, Shashank Hambarde, Ferid Murad, Kum Kum Khanna, Tej K. Pandita, Walter N. Hittelman, E. Brian Butler, Raj K. Pandita |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
induced pluripotent stem cells DNA damage DNA repair Cellular differentiation RAD51 homologous recombination Biology DNA damage response Biochemistry Article 03 medical and health sciences nitric oxide Genetics Humans Induced pluripotent stem cell lcsh:QH301-705.5 Cells Cultured lcsh:R5-920 DNA damaging agents Recombinational DNA Repair Cell Differentiation Cell Biology embryonic stem cells DNA repair protein XRCC4 Molecular biology Embryonic stem cell 030104 developmental biology lcsh:Biology (General) Stem cell lcsh:Medicine (General) DNA Damage Nitroso Compounds Developmental Biology |
| Zdroj: | Stem Cell Reports Stem Cell Reports, Vol 9, Iss 5, Pp 1660-1674 (2017) |
| ISSN: | 2213-6711 |
| Popis: | Summary The nitric oxide (NO)-cyclic GMP pathway contributes to human stem cell differentiation, but NO free radical production can also damage DNA, necessitating a robust DNA damage response (DDR) to ensure cell survival. How the DDR is affected by differentiation is unclear. Differentiation of stem cells, either inducible pluripotent or embryonic derived, increased residual DNA damage as determined by γ-H2AX and 53BP1 foci, with increased S-phase-specific chromosomal aberration after exposure to DNA-damaging agents, suggesting reduced homologous recombination (HR) repair as supported by the observation of decreased HR-related repair factor foci formation (RAD51 and BRCA1). Differentiated cells also had relatively increased fork stalling and R-loop formation after DNA replication stress. Treatment with NO donor (NOC-18), which causes stem cell differentiation has no effect on double-strand break (DSB) repair by non-homologous end-joining but reduced DSB repair by HR. Present studies suggest that DNA repair by HR is impaired in differentiated cells. Graphical Abstract Highlights • Spontaneous and S-phase-specific chromosome aberrations in differentiated cells • Higher frequency of residual γ-H2AX foci after exposure to DNA-damaging agents • Higher frequency of cells with 53BP1 and RIF1 co-localization in differentiated cells • Higher frequency of cells with a reduced number of RAD51 or BRCA1 foci Mujoo and colleagues demonstrate that ESC- or iPSC-derived differentiated cells exhibit higher frequency of residual DNA damage, increased 53BP1 foci and S-phase-specific chromosomal aberrations, and reduced formation of RAD51 or BRCA1 foci. Differentiated cells also had relatively increased stalled DNA replication forks and decreased firing of new replication origins. NO donor treatment decreased DSB repair by HR but not by NHEJ. |
| Databáze: | OpenAIRE |
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