PARENT SESSION
9:00 AM to 11:00 AM
Wednesday, April 24, 2002
Symposium 21
Role of ATM and ATR
Room: Nevada 6-7
Chair: Jung, Mira22Department of Radiation Medicine, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington DC, DC, Co-Chair: Lavin, Maritn33Queensland Institute of Medical REsearch, Bancroft Centre, GPO Royal Brisbane Hospital, Herston, Brisbane, Queensland, Australia
Speakers: Lavin, Martin4; Jung, Mira5; Cimprich, Karlene64Queensland Institute of Medical Research, Bancroft Centre, GPO Royal Brisbane Hospital, Herston, Brisbane, Queensland, Australia5Department of Radiation Medicine, Georgetown University School of Medicine, 3970 Reservoir Road, NW, Washington DC, DC6Department of Molecular Pharmacology, Stanford University School of Medicine, Palo Alto, California
(S21-2) Role of ATM in Chromatin Modification.
Jung, Mira*,1, 1 Department of Radiation Medicine, Georgetown University School of Medicine, Washington, DC
ABSTRACT-
In principle, the DNA-templated processes (transcription, replication, recombination, repair, and segregation) deal with DNA packaged into chromatin. Chromatin structure is regulated through covalent modification of histones and non-histone proteins, including acetylation, deacetylation, phosphorylation, methylation, poly-ADP ribosylation, and ubiquitination. Such modifications are known to be key mechanisms involved in the arrest of cell cycle progression, induction of the transcription of specific genes, and activation of the DNA repair machinery in the responses of cells to DNA damaging reagents. A significant line of evidence has suggested that structural alterations in the chromatin of AT cells may play an important role in AT radiosensitivity. Recently, we have demonstrated that ATM associates with histone deacetylase 1 (HDAC1) in vivo, that the resulting complex exhibits histone deacetylase activity, and that the extent of this association is increased in cells exposed to ionizing radiation. The data show that mutations in the atm gene affect the interaction between ATM and HDAC1 and thereby prevent the increase in histone deactylase activity apparent in control cells after exposure to ionizing radiation. This observation is consistent with previous studies showing that ATM is associated with chromatin, and that decondensation of chromatin increases the radiosensitivity of DNA with respect to formation of double-strand breaks. Therefore, we postulate that AT cells exhibit an increased susceptibility to radiation-induced DNA damage because of dysfunction of ATM as a regulator of DNA packaging into chromatin and as a monitor of chromosomal integrity. Although the mechanism by which ATM affects the acetylation status of the histone associated with chromatin is the subject of further investigations, these results reveal a new role for ATM in the cellular response to ionizing radiation-induced DNA damage.
KEYWORDS: ATM, chromatin modification, ataxia-telangiectasia, histon deacetylase