Chromosomal end fusion resulting from telomere erosion increases susceptibility to radiation via multinucleation: effect of p53.
Loss of p53 tumor suppressor facilitates acquisition of telomerase activity. In fact, both p53 inactivation and telomerase activation are frequently found in human cancers. p53 inactivation, however, eliminates or attenuates the biological responses to telomerase inhibition and the eventual telomere erosion. We show that telomere erosion can increase the susceptibility to radiation, irrespective of p53 status. Both telomerase inhibition and critically shortened telomere with significant change of chromosomal end-to-end fusion were essential for the enhancement of radiosensitivity. The enhancement was correlated with greater formation of multinucleated cells. p53 inactivation did not eliminate the observed generation of chromosomal fusion and multinucleation, and the resulting increased susceptibility to radiation, as opposed to the previously proved role of p53 in mediating cellular responses to telomere dysfunction. The present findings suggest the importance of chromosomal end fusion in modulating radiosensitivity rather than p53 DNA damage signaling. Thus, the suggested anticancer radiotherapeutic strategy combined with telomerase inhibition could clinically be applicable to cancers, irrespective of p53 status.
Ju
Yeun-Jin
YJ
Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
Park
Jeong Eun
JE
Juhn
Kyoung Mi
KM
Jeong
Jaemin
J
Yun
Miyong
M
Park
Myung-Jin
MJ
Park
Gil-Hong
GH
Choi
Kang-Yell
KY
Cho
Myung-Haeng
MH
Wong
Kwok-Kin
KK
Park
Won-Bong
WB
Lee
Kee-Ho
KH
D000818:Animals; D016923:Cell Death; D002875:Chromosomes / Q000235:genetics*; D042822:Genomic Instability; D051379:Mice; D008938:Mitosis; D011836:Radiation Tolerance / Q000235:genetics; D011995:Recombination, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D019098:Telomerase