DNA damage sensing by the ATM and ATR kinases.
Alexandre Maréchal,Lee Zou +1 more
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TLDR
The recent findings and current models of how ATM and ATR senseDNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR are discussed.Abstract:
In eukaryotic cells, maintenance of genomic stability relies on the coordinated action of a network of cellular processes, including DNA replication, DNA repair, cell-cycle progression, and others. The DNA damage response (DDR) signaling pathway orchestrated by the ATM and ATR kinases is the central regulator of this network in response to DNA damage. Both ATM and ATR are activated by DNA damage and DNA replication stress, but their DNA-damage specificities are distinct and their functions are not redundant. Furthermore, ATM and ATR often work together to signal DNA damage and regulate downstream processes. Here, we will discuss the recent findings and current models of how ATM and ATR sense DNA damage, how they are activated by DNA damage, and how they function in concert to regulate the DDR.read more
Citations
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Journal ArticleDOI
Causes and consequences of replication stress.
TL;DR: In this paper, the kinase ATR (ATM- and Rad3-related) stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability.
Journal ArticleDOI
Targeting DNA Repair in Cancer: Beyond PARP Inhibitors.
TL;DR: A thorough understanding of DDR pathway complexities must be combined with strategies and lessons learned from the successful registration of PARP inhibitors in order to fully exploit the potential of DDR inhibitors and to ensure their long-term clinical success.
Journal ArticleDOI
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Ruchi Kumari,Parmjit S Jat +1 more
TL;DR: In this article, the molecular mechanisms that underlie cellular senescence and the senescent associated growth arrest with a particular focus on why cells stop dividing, the stability of the growth arrest, the hypersecretory phenotype and how the different pathways are all integrated.
Journal ArticleDOI
RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response.
Alexandre Maréchal,Lee Zou +1 more
TL;DR: The current understanding of the critical functions of the RPA-ssDNA platform in the maintenance of genome stability and its regulation through an elaborate network of covalent modifications is reviewed.
Journal ArticleDOI
CHK2 kinase in the DNA damage response and beyond
TL;DR: The activity of CHK2 in response to DNA damage and in the maintenance of the biological functions in unstressed cells are discussed and their activities are considered in relation to a possible role of CHk2 in tumorigenesis and, as a consequence, in the target of cancer therapy.
References
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Travis H. Stracker,Monica Morales,Suzana S. Couto,Hussein Hussein,John H.J. Petrini,John H.J. Petrini +5 more
TL;DR: Analysis of p53 transcriptional targets and ATM substrates showed that, in contrast to the phenotype of Chk2-/- mice, NBS1ΔC does not impair the induction of proapoptotic genes, and the defects observed in Nbs1Γ/Γ result from impaired phosphorylation of ATM targets including SMC1 and the proap optotic factor, BID.
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Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells
TL;DR: It is reported that the crucial checkpoint signalling proteins—p53, structural maintainance of chromosomes 1 (SMC1), p53 binding protein 1 (53BP1), checkpoint kinase (Chk)1 and Chk2—are phosphorylated rapidly by ATR in an ATM/Mre11/cell‐cycle‐independent manner, albeit at low levels.
Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions
Nozomi Tomimatsu,Bipasha Mukherjee,Katherine Deland,Akihiro Kurimasa,Emma Bolderson,Kum Kum Khanna,Sandeep Burma +6 more
TL;DR: In this paper, the authors examined the contribution of Exo1 to DNA end resection in humans in vivo in response to ionizing radiation (IR) and its relationship with other resection pathways (Mre11-CtIP or BLM/WRN).
Journal ArticleDOI
Phosphorylation of the Budding Yeast 9-1-1 Complex Is Required for Dpb11 Function in the Full Activation of the UV-Induced DNA Damage Checkpoint
Fabio Puddu,Granata M,Lisa di Nola,Alessia Balestrini,Gabriele Piergiovanni,Federico Lazzaro,Michele Giannattasio,Paolo Plevani,Marco Muzi-Falconi +8 more
TL;DR: The data suggest that Dpb11 is held in proximity to damaged DNA through an interaction with the phosphorylated 9-1-1 complex, leading to Mec1-dependent phosphorylation of Rad9, and it is found that the replication factor Dpb 11 is the keystone of this second pathway.
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Three-Dimensional Structure and Regulation of the DNA-Dependent Protein Kinase Catalytic Subunit (DNA-PKcs)
TL;DR: Cryo-electron microscopy is used to generate an approximately 13 A three-dimensional map of DNA-PKcs, revealing the overall architecture and topology of the 4128 residue polypeptide chain and allowing location of domains.
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