Structural basis of the (in)activity of the apical DNA damage response kinases ATM, ATR and DNA-PKcs

Jansma, Marijke; Hopfner, Karl‐Peter

doi:10.1016/j.pbiomolbio.2020.10.009

Cited by 9 publications

(5 citation statements)

References 72 publications

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“…This situation is rapidly changing with the increasing use of cryo-EM to tackle full-length kinases and their complexes, as exemplified by the progress understanding the regulation of DNA damage response kinases (reviewed by Ref. ( 108 )). Artificial intelligence–based methods have revolutionized the business of protein structure prediction, and structural models are now available for the entire human kinome ( https://alphafold.ebi.ac.uk/ ).…”

Section: Discussionmentioning

confidence: 99%

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Arter

Trask

Ward

et al. 2022

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Arter

Trask

Ward

et al. 2022

Journal of Biological Chemistry

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“…Indeed, PIKKs bind to and are regulated by interacting proteins, with which they form large and dynamic assemblies. In addition, some PIKKs contain an autoregulatory element, particularly in the variable region connecting the kinase and FATC domains, that is known as the PIKK-regulatory domain (PRD) ( Baretić and Williams, 2014 ; Imseng et al, 2018 ; Jansma and Hopfner, 2021 ). Finally, the kinase domains of PIKKs have been the target of numerous efforts in the development of specific inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8

Langer

Bonneau

Gat

et al. 2021

eLife

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The PI3K-related kinase (PIKK) SMG1 monitors progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analogue at overall resolutions ranging from 2.8 to 3.6 Å. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al. 2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.

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“…If the DNA damage signals continue, the cells select to avoid the replication of mutated or damaged genome rather they prefer to promote the processes leading cell cycle arrest of apoptosis [313,314]. Signaling cascades by the detection of damaged DNA are initiated by the activation of MRN (MRE11/RAD50/NBS1) complex subsequent activation of PIKKs (phosphatidylinositol 3-kinase-like kinases) ATM (ataxia-telangiectasia mutated), ATR (ATM-related kinase) [315][316][317]. ATM and ATR are activated by DNA DSBs and stalled replication forks respectively.…”

Section: Genomic Instability and Oxidative Stress In Longevity Of Lif...mentioning

confidence: 99%

Genes and Longevity of Lifespan

Bin-Jumah

Nadeem

Gilani

et al. 2022

IJMS

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Aging is a complex process indicated by low energy levels, declined physiological activity, stress induced loss of homeostasis leading to the risk of diseases and mortality. Recent developments in medical sciences and an increased availability of nutritional requirements has significantly increased the average human lifespan worldwide. Several environmental and physiological factors contribute to the aging process. However, about 40% human life expectancy is inherited among generations, many lifespan associated genes, genetic mechanisms and pathways have been demonstrated during last decades. In the present review, we have evaluated many human genes and their non-human orthologs established for their role in the regulation of lifespan. The study has included more than fifty genes reported in the literature for their contributions to the longevity of life. Intact genomic DNA is essential for the life activities at the level of cell, tissue, and organ. Nucleic acids are vulnerable to oxidative stress, chemotherapies, and exposure to radiations. Efficient DNA repair mechanisms are essential for the maintenance of genomic integrity, damaged DNA is not replicated and transferred to next generations rather the presence of deleterious DNA initiates signaling cascades leading to the cell cycle arrest or apoptosis. DNA modifications, DNA methylation, histone methylation, histone acetylation and DNA damage can eventually lead towards apoptosis. The importance of calorie restriction therapy in the extension of lifespan has also been discussed. The role of pathways involved in the regulation of lifespan such as DAF-16/FOXO (forkhead box protein O1), TOR and JNK pathways has also been particularized. The study provides an updated account of genetic factors associated with the extended lifespan and their interactive contributory role with cellular pathways.

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Structural basis of the (in)activity of the apical DNA damage response kinases ATM, ATR and DNA-PKcs

Cited by 9 publications

References 72 publications

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Structural features of the protein kinase domain and targeted binding by small-molecule inhibitors

Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8

Genes and Longevity of Lifespan

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