The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining
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The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining. / Mansour Khalfallah, Wael Yassin; Borgmann, K; Petersen, Cordula; Dikomey, Ekkehard; Dahm-Daphi, Jochen.
in: DNA REPAIR, Jahrgang 12, Nr. 12, 01.12.2013, S. 1134-42.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The absence of Ku but not defects in classical non-homologous end-joining is required to trigger PARP1-dependent end-joining
AU - Mansour Khalfallah, Wael Yassin
AU - Borgmann, K
AU - Petersen, Cordula
AU - Dikomey, Ekkehard
AU - Dahm-Daphi, Jochen
N1 - Copyright © 2013 Elsevier B.V. All rights reserved.
PY - 2013/12/1
Y1 - 2013/12/1
N2 - Classical-non-homologous end-joining (C-NHEJ) is considered the main pathway for repairing DNA double strand breaks (DSB) in mammalian cells. When C-NHEJ is defective, cells may switch DSB repair to an alternative-end-joining, which depends on PARP1 and is more erroneous. This PARP1-EJ is suggested to be active especially in tumor cells contributing to their genomic instability. Here, we define conditions under which cells would switch the repair to PARP1-EJ. Using the end jining repair substrate pEJ, we revealed that PARP1-EJ is solely used when Ku is deficient but not when either DNA-PKcs or Xrcc4 is lacking. In the latter case, DSB repair, however, could be shuttled to PARP1-EJ after additional Ku80 down-regulation, which partly rescued the DSB repair in these mutants. We demonstrate here that PARP-EJ may work on DSB ends at high fidelity manner, as evident from the unchanged efficiency upon blocking end resection by either roscovitin or mirin. Furthermore, we demonstrate for that PARP-EJ is likewise involved in the repair of multiple DSBs (I-PpoI- and IR-induced). Importantly, we identified a chromatin signature associated with the switch to PARP1-EJ which is characterized by a strong enrichment of both PARP1 and LigIII at damaged chromatin. Together, these data indicate that Ku is the main regulator for the hierarchal organization between C-NHEJ and PARP1-EJ.
AB - Classical-non-homologous end-joining (C-NHEJ) is considered the main pathway for repairing DNA double strand breaks (DSB) in mammalian cells. When C-NHEJ is defective, cells may switch DSB repair to an alternative-end-joining, which depends on PARP1 and is more erroneous. This PARP1-EJ is suggested to be active especially in tumor cells contributing to their genomic instability. Here, we define conditions under which cells would switch the repair to PARP1-EJ. Using the end jining repair substrate pEJ, we revealed that PARP1-EJ is solely used when Ku is deficient but not when either DNA-PKcs or Xrcc4 is lacking. In the latter case, DSB repair, however, could be shuttled to PARP1-EJ after additional Ku80 down-regulation, which partly rescued the DSB repair in these mutants. We demonstrate here that PARP-EJ may work on DSB ends at high fidelity manner, as evident from the unchanged efficiency upon blocking end resection by either roscovitin or mirin. Furthermore, we demonstrate for that PARP-EJ is likewise involved in the repair of multiple DSBs (I-PpoI- and IR-induced). Importantly, we identified a chromatin signature associated with the switch to PARP1-EJ which is characterized by a strong enrichment of both PARP1 and LigIII at damaged chromatin. Together, these data indicate that Ku is the main regulator for the hierarchal organization between C-NHEJ and PARP1-EJ.
U2 - 10.1016/j.dnarep.2013.10.005
DO - 10.1016/j.dnarep.2013.10.005
M3 - SCORING: Journal article
C2 - 24210699
VL - 12
SP - 1134
EP - 1142
JO - DNA REPAIR
JF - DNA REPAIR
SN - 1568-7864
IS - 12
ER -
