Small molecule-based reversible reprogramming of cellular lifespan.
Most somatic cells encounter an inevitable destiny, senescence. Little progress has been made in identifying small molecules that extend the finite lifespan of normal human cells. Here we show that the intrinsic 'senescence clock' can be reset in a reversible manner by selective modulation of the ataxia telangiectasia-mutated (ATM) protein and ATM- and Rad3-related (ATR) protein with a small molecule, CGK733. This compound was identified by a high-throughput phenotypic screen with automated imaging. Employing a magnetic nanoprobe technology, magnetism-based interaction capture (MAGIC), we identified ATM as the molecular target of CGK733 from a genome-wide screen. CGK733 inhibits ATM and ATR kinase activities and blocks their checkpoint signaling pathways with great selectivity. Consistently, siRNA-mediated knockdown of ATM and ATR induced the proliferation of senescent cells, although with lesser efficiency than CGK733. These results might reflect the specific targeting of the kinase activities of ATM and ATR by CGK733 without affecting any other domains required for cell proliferation.
Won
Jaejoon
J
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea.
Kim
Mina
M
Kim
Nuri
N
Ahn
Jin Hee
JH
Lee
Woo Gil
WG
Kim
Sung Soo
SS
Chang
Ki-Young
KY
Yi
Yong-Weon
YW
Kim
Tae Kook
TK
D064007:Ataxia Telangiectasia Mutated Proteins; D044482:Benzeneacetamides / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013890:Thiourea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D044482:Benzeneacetamides; C512273:CGK 733; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D013890:Thiourea