作者
Sahra Bodo, Cécile Campagne, Tin Htwe Thin, Daniel S Higginson, H Alberto Vargas, Guoqiang Hua, John D Fuller, Ellen Ackerstaff, James Russell, Zhigang Zhang, Stefan Klingler, HyungJoon Cho, Matthew G Kaag, Yousef Mazaheri, Andreas Rimner, Katia Manova-Todorova, Boris Epel, Joan Zatcky, Cristian R Cleary, Shyam S Rao, Yoshiya Yamada, Michael J Zelefsky, Howard J Halpern, Jason A Koutcher, Carlos Cordon-Cardo, Carlo Greco, Adriana Haimovitz-Friedman, Evis Sala, Simon N Powell, Richard Kolesnick, Zvi Fuks
发表日期
2019/2/1
期刊
The Journal of clinical investigation
卷号
129
期号
2
页码范围
786-801
出版商
American Society for Clinical Investigation
简介
Tumor cure with conventional fractionated radiotherapy is 65%, dependent on tumor cell–autonomous gradual buildup of DNA double-strand break (DSB) misrepair. Here we report that single-dose radiotherapy (SDRT), a disruptive technique that ablates more than 90% of human cancers, operates a distinct dual-target mechanism, linking acid sphingomyelinase–mediated (ASMase-mediated) microvascular perfusion defects to DNA unrepair in tumor cells to confer tumor cell lethality. ASMase-mediated microcirculatory vasoconstriction after SDRT conferred an ischemic stress response within parenchymal tumor cells, with ROS triggering the evolutionarily conserved SUMO stress response, specifically depleting chromatin-associated free SUMO3. Whereas SUMO3, but not SUMO2, was indispensable for homology-directed repair (HDR) of DSBs, HDR loss of function after SDRT yielded DSB unrepair, chromosomal …
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S Bodo, C Campagne, TH Thin, DS Higginson… - The Journal of clinical investigation, 2019