relationships at low dose IR Dik C. van Gent, Erasmus MC Modeling - - PowerPoint PPT Presentation

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relationships at low dose ir dik c van gent erasmus mc
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relationships at low dose IR Dik C. van Gent, Erasmus MC Modeling - - PowerPoint PPT Presentation

Jan 11, 2023 14 likes •178 views

Linear and non-linear dose-effect relationships at low dose IR Dik C. van Gent, Erasmus MC Modeling of the dose-response curve LNT, threshold, hypersensitive, hormesis? What can we measure at low dose? - DNA repair (linear 10-1000 mGy) -

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Linear and non-linear dose-effect relationships at low dose IR Dik C. van Gent, Erasmus MC

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Modeling of the dose-response curve

LNT, threshold, hypersensitive, hormesis? What can we measure at low dose?

  • DNA repair (linear 10-1000 mGy)
  • micronuclei (linear)
  • chromosomal translocation (linear)

What about uptake extrachromosomal DNA? What about transcriptional responses?

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Random integration assay

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☢

137Cs

75% attenuator

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Repair mutants behave like wt

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H2AX is required for stimulation

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WT Ubi mutants Phospho mutants

H2AX is required for stimulation

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Plateau in dose-response

IR dose

0.005 Gy ~5-10x ~0.5-1 Gy

relative integration

~0.2 Gy ~2x

v

Induction of alternative EJ?

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IR DNA double strand breaks Apoptosis or senescence Aging/age related diseases Cell cycle checkpoints

Regulation of the DNA damage response

Gene expression changes Growth status Oxidative damage?

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Double-strand break repair pathways

Homologous Recombination DNA end-joining (NHEJ) end processing RAD54 DNA-PK

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Low dose gene expression profiles

0.2 Gy 0 Gy

Mice irradiated 0.2 Gy, 0.2 Gy/hr 2 hours later, liver isolated mRNA isolation Micro array analysis Significant genes

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DSB induced genes

Known Responsive genes:

  • Gadd45a/b
  • P21 (CDKN1A)
  • Sesn2
  • cycB (Ccnb1)
  • Puma (Bbc3)
  • Atf3
  • DDB2
  • MDM2
  • BAG3
  • SLUG (Snai2)

WT DNA-PK Rad54 Rad54/ DNA-PK Fold induction IR responsive gene Untreated 0.2 Gy IR

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Tp53 regulation

WT WT Rad5 4

p53 Cyclin G1 ATM PP2A MDM2

phosphorylation degradation stimulation dephosphorylation transcription

All genes that downregulate p53 are upregulated! P21 etc

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IR

DNA double strand breaks ERK signaling NFκB pathway

Regulation of gene expression after IR

Acute phase response p53 Other damage Lipid metabolism More, e.g. splicing?

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P21 reporter mice

unirradiated 0.2 Gy, 4 hours 0.2 Gy, 24 hours No luciferase Wt RAD54 DNA-PK double No luciferase Wt RAD54 DNA-PK double No luciferase Wt RAD54 DNA-PK double

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  • Dept. of Genetics

Stefan Sigurdsson

Alex Zelensky Mascha Schoonakkers Jeroen Essers Paula van Heijningen Ricardo Leite Yanto Ridwan Roland Kanaar Jan Hoeijmakers Dik van Gent Marjolein Sutmuller René Huiskamp

Department of Radiation & Environment Petten, Netherlands

Sylwia Kabacik Christophe Badie

Health Protection Agency, Didcot, UK

Sigrid Swagemakers

Bioinformatics Center

Colin Henderson Roland Wolf

  • Div. of Cancer Res., univ. Of Dundee, UK