Repair of and checkpoint response to topoisomerase I-mediated DNA damage.
Topoisomerase I (Top1) catalyzes two transesterification reactions: single-strand DNA cleavage and religation that are normally coupled for the relaxation of DNA supercoiling in transcribing and replicating chromatin. A variety of endogenous DNA modifications, potent anticancer drugs and carcinogens uncouple these two reactions, resulting in the accumulation of Top1 cleavage complexes. Top1 cleavage complexes damage DNA and kill cells by generating replication-mediated DNA double-strand breaks (DSBs) and by stalling transcription complexes. The repair of Top1-mediated DNA lesions involves integrated pathways that are conserved from yeasts to humans. Top1-mediated DNA damage and cell cycle checkpoint responses can be studied biochemically and genetically in yeast and human cells with known genetic defects. Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells.
Pommier
Yves
Y
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, Building 37, Room 5068, Bethesda, MD 20892-4255, USA. pommier@nih.gov
Redon
Christophe
C
Rao
V Ashutosh
VA
Seiler
Jennifer A
JA
Sordet
Olivier
O
Takemura
Haruyuki
H
Antony
Smitha
S
Meng
LingHua
L
Liao
ZhiYong
Z
Kohlhagen
Glenda
G
Zhang
HongLiang
H
Kohn
Kurt W
KW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004264:DNA Topoisomerases, Type I / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D011995:Recombination, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D004247:DNA; D004264:DNA Topoisomerases, Type I