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Radiosensitivity in Ataxia Telangiectasia

Radiosensitivity in Ataxia Telangiectasia. Ling Li October 25, 2000. Introduction. Ataxia telangiectasia: a human autosomal recessive disorder immune deficiency neurological abnormalities extreme radiosensitivity cell cycle anomalies

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Radiosensitivity in Ataxia Telangiectasia

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  1. Radiosensitivity in Ataxia Telangiectasia Ling Li October 25, 2000

  2. Introduction • Ataxia telangiectasia: a human autosomal recessive disorder immune deficiency neurological abnormalities extreme radiosensitivity cell cycle anomalies predisposition to lymphoid and other malignancies • incidence of AT is 1 in 40, 000 to 1 in 100, 000

  3. The history of AT studies • 1941: first description of AT • 1957: characterized as a separated disease • 1988: mapping of the AT gene to chromosome 11q22-23 • 1995: clone of AT mutated gene (ATM)

  4. Basis of radiosensitivity (I)—with sparsely ionizing radiation AT11LO AT2LO CRL1343 HF19 normal human strain Three AT strains

  5. Basis of radiosensitivity (I)—with sparsely ionizing radiation • After irradiation, normal cells held in a non-growing state have some recovery (or sparing) from lethal effect, while AT cell lines show little or no recovery • Irradiation at low dose-rates shows a very large sparing effect on normal cells, while no or little effect on AT cell

  6. Basis of radiosensitivity (I)—with densely ionizing radiation • Compared to sparsely ionizing radiation ( e.g. x-ray), there is less difference in the damage from densely ionizing radiation between AT cells and normal cells

  7. Basis of radiosensitivity (I)— summary • All of these studies are consistent with an inability of AT cells to recover from radiation damage, and show that the defect cannot be abrogated simply by allowing more time for damage restitution.

  8. Basis of radiosensitivity (II) —chromosome aberration • Break repair a significantly elevated fraction of unrepaired chromosomal breaks remain in AT cells after irradiation. AT cell: O GM-1525C  GM-0717A normal cells 3590P Cell irradiated with 4 Gy

  9. Basis of radiosensitivity (II)—DNA breaks • Mis-rejoining the frequency of mis-rejoining in extracts from AT cell lines is about 20-fold higher than in extracts from normal cell lines • Resistant DNA synthesis normal cells show a rapid inhibition of DNA synthesis after irradiation, while AT cells have a delay and/or much reduced inhibition

  10. Cell cycle control cyclin A,B +Cdc2 cyclin D+ Cdk2,4,6 G2 M G1 cyclin A +Cdk2 p21 S cyclin E+Cdk2 p21+p27 Rb phosphorylation

  11. Cell cycle control and radiosensitivity DNA Damage induction of p53 induction of p21 PCNA-DNA polymerase d Cyclin D,E/CDK2 Cyclin A, B /CDK2 Arrest in G1 if inhibited by p21 DNA replication inhibited Arrest in G2/M G1 phase cells S phase cells G2 phase cells G1/S G2/M

  12. Cell cycle control and radiosensitivity • Defect in G1/S checkpoint DNA damage in AT cell inadequate p53 response less increase in p21 activity reduced inhibition of cyclin E-cdk2 cell progress from G1 to S phase is not delayed • Defect in G2/M checkpoint • the potential role of p53 in G2/M checkpoint (?) • no increase in p21 associated with either cyclinA-cdk2 or cyclinB-cdk2

  13. Cell cycle control and radiosensitivity— Summary • AT cells: not arrested at either the G1/S or G2/M checkpoint after exposure to radiation • The defect in cell cycle control in AT cell is linked to p53.

  14. The ATM gene • The gene was cloned as a 5.9 kb partial cDNA and was found to be mutated in 10 patients. • ORF (open reading frame) of the ATM gene is 9.168 kb and the size of the protein is ~ 350 kDa

  15. ATM protein • The ATM gene encodes for a protein related to a family of yeast and mammalian proteins containing a phosphatidylinositol 3-kinase (PI3-kinase) domain. • ATM proteins are found predominantly in the nucleus.

  16. ATM protein • PI3-Kinase proteins • Composed of a catalytic and a regulatory subunit • Phosphorylating both lipid and protein substrates • Some are involved in cell cycle checkpoint control in response to DNA damage Mec1p (S. cerevisiae) Rad3 (S. pombe) mei41 (D. melanogaster)

  17. ATM protein • ATM homologous protein • DNA-dependent protein kinase (DNA-PK) • DNA-PK • a sensor of DNA damage • phosphorylates DNA-bound substrates • two components: catalytic subunit (DNA-PK CS) DNA -binding component (Ku) • cells deficient in DNA-PK are defective in rejoining DNA breaks, hypersensitive to ionizing radiation

  18. Conclusion • ATM is involved in the cell cycle control through p53 • ATM may assist repairing DNA damage.

  19. Future applications • Gene therapy in cancer • introduction of antisense constructs to reduce ATM gene products • overexpression of cDNA fragments to compete for interaction with other proteins

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