TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks
Allbwn ymchwil: Cyfraniad at gyfnodolyn › Erthygl › adolygiad gan gymheiriaid
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Yn: DNA Repair, Cyfrol 6, Rhif 10, 01.10.2007, t. 1485-95.
Allbwn ymchwil: Cyfraniad at gyfnodolyn › Erthygl › adolygiad gan gymheiriaid
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T1 - TDP1 facilitates repair of ionizing radiation-induced DNA single-strand breaks
AU - El-Khamisy, Sherif F
AU - Hartsuiker, Edgar
AU - Caldecott, Keith W
PY - 2007/10/1
Y1 - 2007/10/1
N2 - Tyrosyl DNA phosphodiesterase-1 (TDP1) is the gene product mutated in spinocerebellar ataxia with axonal neuropathy1 (SCAN1). SCAN1 is a hereditary ataxia that lacks extra-neurological phenotype, pointing to a critical role for TDP1 in the nervous system. Recently, we showed that TDP1 is associated with the DNA single-strand break (SSBR) repair machinery through an interaction with DNA ligase 3alpha (Lig3alpha) and that SCAN1 cells are defective in the repair of chromosomal DNA single-strand breaks (SSBs) arising from abortive Topoisomerase 1 (Top1)-DNA intermediates. Here we demonstrate that TDP1 is also required for the repair of SSBs induced by ionizing radiation (IR), though not measurably for IR-induced DNA double-strand breaks (DSBs). In addition, we provide evidence that abortive Top1 cleavage complexes are processed by the proteasome prior to the action of TDP1 in vivo, and we exploit this observation to show that the SSBR defect in SCAN1 following IR reflects, in part at least, the presence of IR-induced protein-DNA cross-links. Finally we show that TDP1 activity at abortive Top1-SSBs is stimulated by XRCC1/Lig3alpha in vitro. These data expand the type of SSBs processed by TDP1 to include those induced by ionizing radiation, and raise the possibility that TDP1 inhibitors may improve radiotherapy.
AB - Tyrosyl DNA phosphodiesterase-1 (TDP1) is the gene product mutated in spinocerebellar ataxia with axonal neuropathy1 (SCAN1). SCAN1 is a hereditary ataxia that lacks extra-neurological phenotype, pointing to a critical role for TDP1 in the nervous system. Recently, we showed that TDP1 is associated with the DNA single-strand break (SSBR) repair machinery through an interaction with DNA ligase 3alpha (Lig3alpha) and that SCAN1 cells are defective in the repair of chromosomal DNA single-strand breaks (SSBs) arising from abortive Topoisomerase 1 (Top1)-DNA intermediates. Here we demonstrate that TDP1 is also required for the repair of SSBs induced by ionizing radiation (IR), though not measurably for IR-induced DNA double-strand breaks (DSBs). In addition, we provide evidence that abortive Top1 cleavage complexes are processed by the proteasome prior to the action of TDP1 in vivo, and we exploit this observation to show that the SSBR defect in SCAN1 following IR reflects, in part at least, the presence of IR-induced protein-DNA cross-links. Finally we show that TDP1 activity at abortive Top1-SSBs is stimulated by XRCC1/Lig3alpha in vitro. These data expand the type of SSBs processed by TDP1 to include those induced by ionizing radiation, and raise the possibility that TDP1 inhibitors may improve radiotherapy.
KW - Base Sequence
KW - DNA
KW - DNA Damage
KW - DNA Primers
KW - DNA Repair
KW - Humans
KW - Phosphoric Diester Hydrolases
KW - Radiation, Ionizing
KW - Recombinant Proteins
KW - Journal Article
U2 - 10.1016/j.dnarep.2007.04.015
DO - 10.1016/j.dnarep.2007.04.015
M3 - Article
C2 - 17600775
VL - 6
SP - 1485
EP - 1495
JO - DNA Repair
JF - DNA Repair
SN - 1568-7864
IS - 10
ER -