ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot

Sun, Jiying; Oma, Yukako; Harata, Masahiko; Kono, Kazuteru; Shima, Hiroki; Kinomura, Aiko; Ikura, Tsuyoshi; Suzuki, Hidekazu; Mizutani, Shuki; Kanaar, Roland; Tashiro, Satoshi

doi:10.1371/journal.pone.0013554

Cited by 17 publications

(24 citation statements)

References 43 publications

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“…Treatment with DNA-PKi prior to irradiation did not alter Rad51 ability to resolve DNA DSB. Instead, the HR repair kinetics was similar to irradiated only samples with a return to basal levels of Rad51 foci positive cells by 24 h. The current data sets are similar to ATM knock-out cells with increased Rad51 foci accumulation post-irradiation which resulted in chromosomal abnormalities (Sun et al, 2010). The combined disruption of HR through ATMi and low NHEJ activity in GICs led to accumulation of a substantial number of unrepaired DSBs as indicated by both gH2AX and 53BP1 foci.…”

Section: Discussionsupporting

confidence: 63%

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

et al. 2014

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Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival.

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Section: Discussionsupporting

confidence: 63%

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

et al. 2014

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“…Since a basal level of p53 is required for antioxidant activities in normal cell growth (61), the p53-RPA complex formation may serve to mask this p53 domain and prevent the above-basal levels of free p53 from interrupting normal cellular functions, complementing the MDM2 function of sequestering and inactivating p53. With significant DNA damage, however, cellular p53 is greatly elevated while expression of RPA remains unaffected (62). Here, disruption of the p53-RPA complex may be necessary to free RPA for functioning in DDRs as RPA plays indispensable roles in DNA damage checkpoint and repair pathways.…”

Section: Discussionmentioning

confidence: 99%

DNA-PK, ATM and ATR collaboratively regulate p53–RPA interaction to facilitate homologous recombination DNA repair

Serrano

Dangeti

et al. 2012

Oncogene

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Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are two distinct DNA double-strand break (DSB) repair pathways. Here we report that DNA-dependent protein kinase (DNA-PK), the core component of NHEJ, partnering with DNA-damage checkpoint kinases ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR), regulates HR repair of DSBs. The regulation was accomplished through modulation of the p53 and replication protein A (RPA) interaction. We show that upon DNA damage, p53 and RPA were freed from a p53-RPA complex by simultaneous phosphorylations of RPA at the N-terminus of RPA32 subunit by DNA-PK and of p53 at Ser37 and Ser46 in a Chk1/Chk2-independent manner by ATR and ATM, respectively. Neither the phosphorylation of RPA nor of p53 alone could dissociate p53 and RPA. Furthermore, disruption of the release significantly compromised HR repair of DSBs. Our results reveal a mechanism for the crosstalk between HR repair and NHEJ through the co-regulation of p53-RPA interaction by DNA-PK, ATM and ATR.

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“…Binding of Replication protein A (RPA) and the chromatin remodeler INO80, which facilitate RAD51 loading on damaged DNA, to the hotspot were also increased by ATM deficiency. Thus, in addition to activating DNA damage signaling, ATM may avert chromosome translocations by preventing excessive loading of recombinational repair proteins onto translocation breakpoint hotspots (Sun et al, 2010 ). In this context it is of interest that reduced ATM levels were found in cycling human HSPCs as compared with cycling mature human peripheral blood lymphocytes (Kraft et al, 2015 ), providing one possible explanation for HSPC proneness to aberrant homologous recombination events at the MLLbcr .…”

Section: How Is Broken Mllbcr Repaired?mentioning

confidence: 99%

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

Gole

Wiesmüller

2015

Front. Cell Dev. Biol.

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Despite manifold efforts to achieve reduced-intensity and -toxicity regimens, secondary leukemia has remained the most severe side effect of chemotherapeutic cancer treatment. Rearrangements involving a short telomeric <1 kb region of the mixed lineage leukemia (MLL) gene are the most frequently observed molecular changes in secondary as well as infant acute leukemia. Due to the mode-of-action of epipodophyllotoxins and anthracyclines, which have widely been used in cancer therapy, and support from in vitro experiments, cleavage of this MLL breakpoint cluster hotspot by poisoned topoisomerase II was proposed to trigger the molecular events leading to malignant transformation. Later on, clinical patient data and cell-based studies addressing a wider spectrum of stimuli identified cellular stress signaling pathways, which create secondary DNA structures, provide chromatin accessibility, and activate nucleases other than topoisomerase II at the MLL. The MLL destabilizing signaling pathways under discussion, namely early apoptotic DNA fragmentation, transcription stalling, and replication stalling, may all act in concert upon infection-, transplantation-, or therapy-induced cell cycle entry of hematopoietic stem and progenitor cells (HSPCs), to permit misguided cleavage and error-prone DNA repair in the cell-of-leukemia-origin.

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ATM Modulates the Loading of Recombination Proteins onto a Chromosomal Translocation Breakpoint Hotspot

Cited by 17 publications

References 43 publications

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells

DNA-PK, ATM and ATR collaboratively regulate p53–RPA interaction to facilitate homologous recombination DNA repair

Leukemogenic rearrangements at the mixed lineage leukemia gene (MLL)—multiple rather than a single mechanism

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