Structures and regulations of ATM and ATR, master kinases in genome integrity

Williams, Rhys M.; Yates, Luke A.; Zhang, Xiaodong

doi:10.1016/j.sbi.2019.12.010

Cited by 35 publications

(17 citation statements)

References 34 publications

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“…Therefore, assembly of mTORC1 requires the concerted action of CCT (for proper C-terminal folding of Raptor and mLst8) and the Hsp90 TTT-R2TP complex (for mTOR folding). The two-lobed PIKK KD presents several conserved elements: the ATP loop in the N-lobe, and the catalytic and activation loops, as well as the PIKK-regulatory domain (PRD), in the C-lobe [110] ( Figure 8B). The PRD consists of two conserved helices (kinase (K) α9 and Kα10) connected by a divergent loop, termed the PRD insert (PRD-I) [110].…”

Section: Beyond Cell Growth: Tor As a Pikkmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

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The Target of Rapamycin (TOR) is a highly conserved serine/threonine protein kinase that performs essential roles in the control of cellular growth and metabolism. TOR acts in two distinct multiprotein complexes, TORC1 and TORC2 (mTORC1 and mTORC2 in humans), which maintain different aspects of cellular homeostasis and orchestrate the cellular responses to diverse environmental challenges. Interest in understanding TOR signaling is further motivated by observations that link aberrant TOR signaling to a variety of diseases, ranging from epilepsy to cancer. In the last few years, driven in large part by recent advances in cryo-electron microscopy, there has been an explosion of available structures of (m)TORC1 and its regulators, as well as several (m)TORC2 structures, derived from both yeast and mammals. In this review, we highlight and summarize the main findings from these reports and discuss both the fascinating and unexpected molecular biology revealed and how this knowledge will potentially contribute to new therapeutic strategies to manipulate signaling through these clinically relevant pathways.

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Section: Beyond Cell Growth: Tor As a Pikkmentioning

confidence: 99%

Structural Insights into TOR Signaling

Tafur

Kefauver

Loewith

2020

Genes

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“…1c). Moreover, the PIKK regulatory domain (PRD, aa 4009-4039), which is partially disordered in mTOR and SMG1 (Langer et al, 2020;Yang et al, 2017), and closed in ATM, ATR (Jansma et al, 2020;Williams et al, 2020), and in all other DNA-PKcs and DNA-PK complexes, rotated 115° to expose the substrate binding groove. Complex VI also revealed that the activated DNA-PKcs has a potential binding site for inositol hexaphosphate (IP6), which has been shown to activate DNA-PK and NHEJ (Hanakahi et al, 2000).…”

Section: Results Cryoem Structures Of Dna-pkmentioning

confidence: 99%

“…Multiple structures of other PIKK kinases complexed with accessory subunits, activation cofactors, ATP analogs, and even a substrate peptide have been reported, representing either active mTOR and SMG1 (Langer et al, 2020;Yang et al, 2017) or inhibited ATM and ATR (Jansma et al, 2020;Williams et al, 2020). In all cases the role of the HEAT-repeat structures, which is 5 to 9-fold larger than the kinase domain, remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Stretch and Twist of HEAT Repeats Leads to Activation of DNA-PK Kinase

Chen

et al. 2020

Preprint

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Phosphatidylinositol 3-kinase-related kinases (PIKKs) are composed of conserved FAT and kinase domains (FATKIN) along with varied solenoid structures made of HEAT repeats. These kinases are activated in response to cellular stress signals, but the mechanisms governing activation and regulation remain unresolved. For DNA-dependent protein kinase (DNA-PK), all existing structures represent inactive states with resolution limited to 4.3 angstrom at best. Here we report the cryoEM structures of DNA-PKcs (catalytic subunit) bound to a DNA end, or complexed with Ku70/80 and DNA, in both inactive and activated forms at resolutions of 3.7 angstrom overall, and 3.2 angstrom for FATKIN. These structures reveal the sequential transition of DNA-PK from inactive to activated forms. Most notably, activation of the kinase involves previously unknown stretching and twisting within individual solenoid segments and coordinated shifts of neighboring segments in opposite directions. This unprecedented structural plasticity of helical repeats may be a general feature of HEAT-repeat proteins.

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“…The adverse effect of 2μ POL30 and elg1Δ on mcd1-1 mutant cells is consistent with the model that even very moderate levels of PCNA is detrimental to genome maintenance. Mec1 (ATR) and Tel1 (ATM) kinases form parallel DNA damage response pathways [81][82][83][84]. To determine…”

Section: Elevated Levels Of Chromatin-bound Pcna (Via 2μ Pol30) Activmentioning

confidence: 99%

PCNA antagonizes cohesin-dependent roles in genomic stability

Zuilkoski

Skibbens

2020

PLoS ONE

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PCNA sliding clamp binds factors through which histone deposition, chromatin remodeling, and DNA repair are coupled to DNA replication. PCNA also directly binds Eco1/Ctf7 acetyltransferase, which in turn activates cohesins and establishes cohesion between nascent sister chromatids. While increased recruitment thus explains the mechanism through which elevated levels of chromatin-bound PCNA rescue eco1 mutant cell growth, the mechanism through which PCNA instead worsens cohesin mutant cell growth remains unknown. Possibilities include that elevated levels of long-lived chromatin-bound PCNA reduce either cohesin deposition onto DNA or cohesin acetylation. Instead, our results reveal that PCNA increases the levels of both chromatin-bound cohesin and cohesin acetylation. Beyond sister chromatid cohesion, PCNA also plays a critical role in genomic stability such that high levels of chromatin-bound PCNA elevate genotoxic sensitivities and recombination rates. At a relatively modest increase of chromatin-bound PCNA, however, fork stability and progression appear normal in wildtype cells. Our results reveal that even a moderate increase of PCNA indeed sensitizes cohesin mutant cells to DNA damaging agents and in a process that involves the DNA damage response kinase Mec1(ATR), but not Tel1(ATM). These and other findings suggest that PCNA mis-regulation results in genome instabilities that normally are resolved by cohesin. Elevating levels of chromatin-bound PCNA may thus help target cohesinopathic cells linked that are linked to cancer.

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Structures and regulations of ATM and ATR, master kinases in genome integrity

Cited by 35 publications

References 34 publications

Structural Insights into TOR Signaling

Structural Insights into TOR Signaling

Stretch and Twist of HEAT Repeats Leads to Activation of DNA-PK Kinase

PCNA antagonizes cohesin-dependent roles in genomic stability

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