Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl

Chen, Gang; Yuan, Shyng‐Shiou F.; Liu, Wei; Xu, Yiming; Trujillo, Kelly M.; Song, Binwei; Cong, Feng; Goff, Stephen P.; Wu, Yun; Arlinghaus, Ralph B.; Baltimore, David; Gasser, P.; Park, Min; Sung, Patrick; Lee, Eva Y.-H.P.

doi:10.1074/jbc.274.18.12748

Cited by 241 publications

(154 citation statements)

References 37 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…However, whether the repair defects observed in c-AblÀ/À MEFs were mediated by the compromised activation of Atm/Atr needed further investigation. 14,34 Based on these findings, we propose the following model to explain a possible role for c-Abl in cell response to DSBs. Once DSBs occur, Atm is localized onto DSBs and is activated in a MRN complex-dependent but c-Abl independent manner.…”

Section: Discussionmentioning

confidence: 99%

A positive role for c-Abl in Atm and Atr activation in DNA damage response

et al. 2010

View full text Add to dashboard Cite

DNA damage triggers Atm-and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. Cell Death and Differentiation (2011) 18, 5-15; doi:10.1038/cdd.2010; published online 27 August 2010 DNA damage can be caused by exogenous or endogenous factors such as ionizing radiation (IR), chemotherapeutic drugs, and stalled replication forks. 1 It is believed that various DNA lesions are eventually converted to double-stranded breaks (DSBs) and/or single-stranded DNA (ssDNA or SSBs), where sensors, mediators, transducers, and effectors assemble to form nuclear foci, which function as centers of signal propagation. At the core of the signaling network are PI-3 kinase-like kinases (PIKKs), including Atm, Atr and DNA-PKcs. 2 Atm is mainly activated by DSBs, whereas Atr responds to various DNA lesions. 3 Atm and Atr are recruited to the nuclear foci by the MRN (Mre11-Rad50-NBS) complex and ATRIP, respectively, 4,5 where they phosphorylate proteins such as p53, Chk1, Chk2, and H2AX, to activate cell cycle checkpoints and/or induce apoptosis. 6 Phosphorylation of Chk1 and Chk2 by Atr and Atm is facilitated by a group of nuclear foci proteins called mediators, for example, Brca1, TopBP1, and 53BP1. Furthermore, the nuclear foci also function as repair centers. 7 DSB repair is believed to involve an Atm to Atr switch. 8,9 Atm is first recruited to DSBs and ssDNA is later generated by resection of the DNA ends, where Atr can be assembled and activated. Thus, there exists a complex functional interaction between these two PIKKs. 10 Although several proteins have been reported to activate Atm or Atr, 11,12 the initial activation of Atm/Atr and the regulation of their activities in the process of DNA repair are poorly understood. 13,14 The c-Abl proto-oncogene encodes a non-receptor tyrosine kinase that is essential for perinatal survival in ...

show abstract

Section: Discussionmentioning

confidence: 99%

A positive role for c-Abl in Atm and Atr activation in DNA damage response

et al. 2010

View full text Add to dashboard Cite

show abstract

“…However, at concentrations resulting in a significant inhibition of DNA-PK-dependent NHEJ, wortmannin also inhibits ATM (Sarkaria et al, 1998). It has been shown that ATM regulates other proteins known to play a role in DNA-repair, cell-cycle regulation and radiation sensitivity, including p53, CHK2, BRCA1 and NBS1 (Canman et al, 1998;Cortez et al, 1999), and is required for the assembly of Rad51 foci (Chen et al, 1999;Yuan et al, 2003). Therefore, wortmannin should not only affect NHEJ through inhibition of DNA-PK activity in NSCLC cell lines , but also HR via inhibition of ATM-dependent formation of Rad51 foci.…”

Section: -Test)mentioning

confidence: 99%

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

et al. 2005

View full text Add to dashboard Cite

The aim of the present work was to study the role of Rad51-dependent homologous recombination in the radiation response of non-small-cell lung cancer (NSCLC) cell lines. A dose-and time-dependent increase in the formation of Rad51 and g-H2AX foci with a maximum at about 4 and 1 h after irradiation, followed by a decrease, has been found. The relative fraction of cells with persisting Rad51 foci was 20 -30% in radioresistant and 60 -80% in radiosensitive cell lines. In comparison, a higher fraction of residual Dsb was evident in cell lines with nonfunctional p53. Transfection with As-Rad51 significantly downregulates radiation-induced formation of Rad51 foci and increases apoptosis, but did not influence the rejoining of DNA double-strand breaks. Interestingly, wortmannin, a well-known inhibitor of nonhomologous end-joining, also inhibits Rad51 foci formation. In general, there was no correlation between the clonogenic survival at 2 Gy and the percentage of initial Rad51 or g-H2AX foci after ionising radiation (IR). The most reliable predictive factor for radiosensitivity of NSCLC cell lines was the relative fraction of Rad51 foci remaining at 24 h after IR. Although most of the Rad51 foci are co-localised with g-H2AX foci, no correlation of the relative fraction of persisting g-H2AX foci and SF2 is evident.

show abstract

“…44 It has been suggested that the IR signaling pathway that includes Atm and c-Abl, is required for modifying Rad51 to be assembled in a repair protein complex. 45 Also, direct interaction was demonstrated between c-Abl and DNA-PK. 31 The latter plays an essential role in DNA recombination.…”

Section: C-abl: Dna-binding and Transcriptionmentioning

confidence: 99%

c-Abl: activation and nuclear targets

2000

View full text Add to dashboard Cite

The c-Abl tyrosine kinase and its transforming variants have been implicated in tumorigenesis and in many important cellular processes. c-Abl is localized in the nucleus and the cytoplasm, where it plays distinct roles. The effects of c-Abl are mediated by multiple protein-protein and protein-DNA interactions and its tyrosine kinase domain. At the biochemical level, the mechanism of c-Abl kinase activation and the identification of its target proteins and cellular machineries have in part been solved. However, the phenotypic outcomes of these molecular events remained in large elusive. c-Abl has been shown to regulate the cell cycle and to induce under certain conditions cell growth arrest and apoptosis. In this respect the interaction of c-Abl with p53 and p73 has attracted particular attention. Recent findings have implicated c-Abl in an ionizing irradiation signaling pathway that elicits apoptosis. In this pathway p73 is an important immediate downstream effector. Here I review the current knowledge about these nuclear processes in which c-Abl is engaged and discuss some of their possible implications on cell physiology. Cell Death and Differentiation (2000) 7, 10 ± 16.

show abstract

Radiation-induced Assembly of Rad51 and Rad52 Recombination Complex Requires ATM and c-Abl

Cited by 241 publications

References 37 publications

A positive role for c-Abl in Atm and Atr activation in DNA damage response

A positive role for c-Abl in Atm and Atr activation in DNA damage response

Targeting of Rad51-dependent homologous recombination: implications for the radiation sensitivity of human lung cancer cell lines

c-Abl: activation and nuclear targets

Contact Info

Product

Resources

About