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Molecular and Cellular Biology, July 2004, p. 6350-6361, Vol. 24, No. 14
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.14.6350-6361.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differentiation-Induced Radioresistance in Muscle Cells

Lucia Latella,1,{dagger} Jiri Lukas,1 Cristiano Simone,2,3 Pier Lorenzo Puri,2,3* and Jiri Bartek1*

Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark,1 Dulbecco Telethon Institute at Fondazione A. Cesalpino, Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome, Italy,2 Clayton Foundation Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, California3

Received 17 July 2003/ Returned for modification 18 August 2003/ Accepted 12 April 2004

DNA damage induces cell cycle arrest and DNA repair or apoptosis in proliferating cells. Terminally differentiated cells are permanently withdrawn from the cell cycle and partly resistant to apoptosis. To investigate the effects of genotoxic agents in postmitotic cells, we compared DNA damage-activated responses in mouse and human proliferating myoblasts and their differentiated counterparts, the myotubes. DNA double-strand breaks caused by ionizing radiation (IR) induced rapid activating autophosphorylation of ataxia-teleangiectasia-mutated (ATM), phosphorylation of histone H2AX, recruitment of repair-associated proteins MRE11 and Nbs1, and activation of Chk2 in both myoblasts and myotubes. However, IR-activated, ATM-mediated phosphorylation of p53 at serine 15 (human) or 18 (mouse) [Ser15(h)/18(m)], and apoptosis occurred in myoblasts but was impaired in myotubes. This phosphorylation could be enforced in myotubes by the anthracycline derivative doxorubicin, leading to selective activation of proapoptotic genes. Unexpectedly, the abundance of autophosphorylated ATM was indistinguishable after exposure of myotubes to IR (10 Gy) or doxorubicin (1 µM/24 h) despite efficient phosphorylation of p53 Ser15(h)/18(m), and apoptosis occurred only in response to doxorubicin. These results suggest that radioresistance in myotubes might reflect a differentiation-associated, pathway-selective blockade of DNA damage signaling downstream of ATM. This mechanism appears to preserve IR-induced activation of the ATM-H2AX-MRE11/Rad50/Nbs1 lesion processing and repair pathway yet restrain ATM-p53-mediated apoptosis, thereby contributing to life-long maintenance of differentiated muscle tissues.

* Corresponding author. Mailing address for Pier Lorenzo Puri: Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Via Castel Romano 100, 00128 Rome, Italy. Phone: 39-06-80319052. Fax: 39-06-80319054. E-mail: plpuri{at}dti.telethon.it. Mailing address for Jiri Bartek: Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen Ø, Denmark. Phone: 45-35-25-73-57. Fax: 45-35-25-77-21. E-mail: bartek{at}biobase.dk.

{dagger} Present address: Dulbecco Telethon Institute at Fondazione A. Cesalpino, Institute of Cell Biology and Tissue Engineering, San Raffaele Biomedical Science Park of Rome, Rome, Italy.

Molecular and Cellular Biology, July 2004, p. 6350-6361, Vol. 24, No. 14
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.14.6350-6361.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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