viral single-strand dna induces p53-dependent apoptosis in human embryonic stem cells病毒细胞凋亡p53-dependent单链dna在人类胚胎干细胞.pdfVIP

Viral Single-Strand DNA Induces p53-Dependent Apoptosis in Human Embryonic Stem Cells 1 4 5 6 1 Matthew L. Hirsch *, B. Matthew Fagan , Raluca Dumitru , Jacquelyn J. Bower , Swati Yadav , Matthew H. Porteus7, Larysa H. Pevny3,5, R. Jude Samulski1,2* 1 Gene Therapy Center, University of North Carolina, Chapel Hill, North Carolina, United States of America, 2 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, United States of America, 3 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America, 4 Human Embryonic Stem Cell Core Facility, University of North Carolina, Chapel Hill, North Carolina, United States of America, 5 Department of Cell and Developmental Biology, Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina, United States of America, 6 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America, 7 Department of Pediatrics-Cancer Biology, Stanford University, Palo Alto, California, United States of America Abstract Human embryonic stem cells (hESCs) are primed for rapid apoptosis following mild forms of genotoxic stress. A natural form of such cellular stress occurs in response to recombinant adeno-associated virus (rAAV) single-strand DNA genomes, which exploit the host DNA damage response for replication and genome persistence. Herein, we discovered a unique DNA damage response induced by rAAV transduction specific to pluripotent hESCs. Within hours following rAAV transduction, host DNA damage signaling was elicited as measured by increased gamma-H2AX, ser15-p53 phosphorylation, and subsequent p