ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Menolfi, Demis; Zha, Shan

doi:10.1007/s42764-019-00003-9

Cited by 12 publications

(10 citation statements)

References 198 publications

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“…The DDR is vigorously activated by the highly cytotoxic DNA double‐strand breaks (DSBs; Goodarzi & Jeggo, 2013; Goldstein & Kastan, 2015). The apical transducers that orchestrate the DSB response are three serine‐threonine protein kinases, ataxia‐telangiectasia, mutated (ATM), ataxia‐telangiectasia and Rad3‐related (ATR) and DNA‐dependent protein kinase (DNA‐PK), which belong to a family of PI3‐kinase‐related protein kinases (PIKKs; Lovejoy & Cortez, 2009; Blackford & Jackson, 2017; Menolfi & Zha, 2019).…”

Section: Introductionmentioning

confidence: 99%

Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress

et al. 2020

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The DNA damage response (DDR) is a complex signaling network that relies on cascades of protein phosphorylation, which are initiated by three protein kinases of the family of PI3‐kinase‐related protein kinases (PIKKs): ATM, ATR, and DNA‐PK. ATM is missing or inactivated in the genome instability syndrome, ataxia‐telangiectasia (A‐T). The relative shares of these PIKKs in the response to genotoxic stress and the functional relationships among them are central questions in the genome stability field. We conducted a comprehensive phosphoproteomic analysis in human wild‐type and A‐T cells treated with the double‐strand break‐inducing chemical, neocarzinostatin, and validated the results with the targeted proteomic technique, selected reaction monitoring. We also matched our results with 34 published screens for DDR factors, creating a valuable resource for identifying strong candidates for novel DDR players. We uncovered fine‐tuned dynamics between the PIKKs following genotoxic stress, such as DNA‐PK‐dependent attenuation of ATM. In A‐T cells, partial compensation for ATM absence was provided by ATR and DNA‐PK, with distinct roles and kinetics. The results highlight intricate relationships between these PIKKs in the DDR.

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Section: Introductionmentioning

confidence: 99%

Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress

et al. 2020

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“…Compared with the structure of DNA-PKcs itself, the N-terminal flexible arm structure of DNA-PKcs moves as a gate ( Figure 3D) for interacting with a DNA bound Ku molecule followed with allosteric conformational change in the kinase domain (38,(46)(47)(48). The key kinase function of DNA-PKcs is the autophosphorylation (including residue S2056) which can induce large conformational change and lead to the dissociation of DNA-PKcs from the Ku bound DNA (23,(49)(50)(51). Mice carrying a catalytic dead DNA-PKcs mutant but not DNA-PKcs null are embryonic lethal because the mutant DNA-PKcs is unable to disassociate from the ends, hence blocking DNA ligation (52).…”

Section: Dna-pkcsmentioning

confidence: 99%

Structural mechanism of DNA-end synapsis in the non-homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends

2019

Biochemical Society Transactions

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Non-homologous end joining (NHEJ) is a major repair pathway for DNA double-strand breaks (DSBs), which is the most toxic DNA damage in cells. Unrepaired DSBs can cause genome instability, tumorigenesis or cell death. DNA end synapsis is the first and probably the most important step of the NHEJ pathway, aiming to bring two broken DNA ends close together and provide structural stability for end processing and ligation. This process is mediated through a group of NHEJ proteins forming higher-order complexes, to recognise and bridge two DNA ends. Spatial and temporal understanding of the structural mechanism of DNA-end synapsis has been largely advanced through recent structural and single-molecule studies of NHEJ proteins. This review focuses on core NHEJ proteins that mediate DNA end synapsis through their unique structures and interaction properties, as well as how they play roles as anchor and linker proteins during the process of ‘bridge over troubled ends'.

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“…2). While ATR is a major sensor functions in the replication stress response (Shubassi et al 2012), ATM mainly senses DSBs and can be activated by other aberrant DNA structures (Roos et al 2016;Menolfi and Zha 2020). ATM activates LKB1 and results in AMPK activation, which in turn phosphorylates the tumor suppressor TSC2, resulting in mTORC1 repression and therefore alleviate its inhibitory effect on autophagy (Alexander et al 2010).…”

Section: Interaction Between Autophagy and Dna Repairmentioning

confidence: 99%

Autophagy and DNA damage repair

Guo

Zhao

2020

GENOME INSTAB. DIS.

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DNA damage occurs frequently resulting from both exogenous and endogenous factors, which induce a series of downstream responses including autophagy and DNA damage repair. In the past few years, increasing evidence has indicated that the interplay between autophagy and DNA damage repair is essential for maintaining genome stability as well as cellular homeostasis, and have significant effects on cell fate. On one hand, autophagy is induced during the process of DNA damage repair, and can act as an upstream factor of DNA damage repair as well. On the other hand, autophagy plays a rather dual role in regulating DNA damage repair, as mild and repairable DNA damage repair can be restored with facilitation of autophagy, hyperactivation of autophagy can be cytotoxic and have negative impact on DNA damage repair. In this article, we review current understandings about the cross talk between autophagy and DNA damage repair, with particular attention to their significance to genome integrity and effects on cell fate.

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ATM, DNA-PKcs and ATR: shaping development through the regulation of the DNA damage responses

Cited by 12 publications

References 198 publications

Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress

Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress

Structural mechanism of DNA-end synapsis in the non-homologous end joining pathway for repairing double-strand breaks: bridge over troubled ends

Autophagy and DNA damage repair

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