ATM and ATR signaling at a glance

Awasthi, Poorwa; Foiani, Marco; Kumar, Amit

doi:10.1242/jcs.188631

Cited by 43 publications

(37 citation statements)

References 116 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activation of Mec1 ATR requires multiple post-translational modifications that integrate chromosomal signals and mechanical stimuli (Awasthi et al., 2016). Deactivation of Mec1 ATR promotes cell-cycle recovery or adaptation (Bartek and Lukas, 2007).…”

Section: Discussionmentioning

confidence: 99%

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

et al. 2017

Self Cite

View full text Add to dashboard Cite

SummaryMec1ATR mediates the DNA damage response (DDR), integrating chromosomal signals and mechanical stimuli. We show that the PP2A phosphatases, ceramide-activated enzymes, couple cell metabolism with the DDR. Using genomic screens, metabolic analysis, and genetic and pharmacological studies, we found that PP2A attenuates the DDR and that three metabolic circuits influence the DDR by modulating PP2A activity. Irc21, a putative cytochrome b5 reductase that promotes the condensation reaction generating dihydroceramides (DHCs), and Ppm1, a PP2A methyltransferase, counteract the DDR by activating PP2A; conversely, the nutrient-sensing TORC1-Tap42 axis sustains DDR activation by inhibiting PP2A. Loss-of-function mutations in IRC21, PPM1, and PP2A and hyperactive tap42 alleles rescue mec1 mutants. Ceramides synergize with rapamycin, a TORC1 inhibitor, in counteracting the DDR. Hence, PP2A integrates nutrient-sensing and metabolic pathways to attenuate the Mec1ATR response. Our observations imply that metabolic changes affect genome integrity and may help with exploiting therapeutic options and repositioning known drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…Both MRI and PET are susceptible to partial volume effects related to variation in extent of hypoxic subregions within and surrounding an imaging voxel. Hypoxic cords surrounding a microvessel have dimensions of a few 10's of microns -far below the spatial resolution of either MRI (mm 3 ) or PET (cm 3 ). However, groups of hypoxic cords tend to occur together.…”

Section: Tumor Hypoxia Imagingmentioning

confidence: 97%

“…Double-strand breaks (DSBs) are the most lethal threats to genomic integrity, and as such mammalian cells have developed complex mechanisms to detect and repair these lesions. With regard to proximal DNA damage sensing, DSBs activate ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3 related (ATR) proteins, which in turn activate two downstream key kinases, checkpoint kinases 1 (Chk1) and 2 (Chk2) (3). The end result is cell cycle arrest and DNA repair, which are closely intertwined.…”

Section: A Overview Of the Key Dna Damage Response Pathwaysmentioning

confidence: 99%

GBM radiosensitizers: dead in the water…or just the beginning?

et al. 2017

View full text Add to dashboard Cite

Abstract:The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Introduction. The finding that most GBMs recur either near or within the primary site after radiotherapy has fueled great interest in the development of radiosensitizers to enhance local control. Unfortunately, decades of clinical trials testing a wide range of novel therapeutic approaches have failed to yield any clinically viable radiosensitizers (1). However, it is well-recognized that temozolomide chemotherapy is administered concurrently with radiotherapy specifically as a radiosensitizer. Furthermore, it can be argued that many of the previous radiosensitizing strategies, for GBM and many other tumor types were not backed by firm pre-clinical evidence supporting a synergistic or additive interaction (2). Another poorly understood variable is lack of blood-brain barrier penetration as potential limitation for treatment efficacy, as until recently most clinical trials did not assess the actual drug levels in GBM tumors. Finally, despite an understanding that DNA repair status was an important variable for radiotherapy treatment responses dating back to the 1970's, the actual DNA repair pathways and proteins were only fully elucidated in the last decade. Here, we present recent progress in the use of small molecule DNA damage response inhibitors as GBM radiosensitizers. In addition, we discuss the latest progress in targeting hypoxia and oxidative stress for GBM radiosensitization. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation

show abstract

“…This clear division of duties is likely to represent an over-simplification, since there is clear evidence of at least partial redundancy between the two proteins, both of which are capable of phosphorylating a range of downstream DDR signalling proteins including Chk1, Chk2 and, indirectly, Wee1 [14]. In line with this, ATR inhibitors have shown exciting radiosensitising properties in a number of different tumour models [15,16] and in the case of the Vertex compound VE-822 the enhancement of tumour growth delay occurred in the absence of any exacerbation of radiation damage to the intestine.…”

Section: Cell Cycle Checkpoint Inhibitorsmentioning

confidence: 99%

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

Chalmers

2016

Clinical Oncology

View full text Add to dashboard Cite

ATM and ATR signaling at a glance

Cited by 43 publications

References 116 publications

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

PP2A Controls Genome Integrity by Integrating Nutrient-Sensing and Metabolic Pathways with the DNA Damage Response

GBM radiosensitizers: dead in the water…or just the beginning?

Science in Focus: Combining Radiotherapy with Inhibitors of the DNA Damage Response

Contact Info

Product

Resources

About