DNA repair, Journal Year: 2022, Volume and Issue: 118, P. 103380 - 103380
Published: July 30, 2022
Language: Английский
MedComm, Journal Year: 2022, Volume and Issue: 3(4)
Published: Nov. 3, 2022
Abstract Protein phosphorylation is an important post‐transcriptional modification involving extremely wide range of intracellular signaling transduction pathways, making it therapeutic target for disease intervention. At present, numerous drugs targeting protein have been developed the treatment various diseases including malignant tumors, neurological diseases, infectious and immune diseases. In this review article, we analyzed 303 small‐molecule kinase inhibitors (PKIs) registered participated in clinical research obtained a database named Kinase Inhibitor Database (PKIDB), 68 approved by Food Drug Administration United States. Based on previous classifications kinases, divided these human kinases into eight groups nearly 50 families, delineated their main regulatory upstream downstream targets. These include: A, G, C (AGC) receptor guanylate cyclase (RGC) group, calmodulin‐dependent (CaMK) CMGC [Cyclin‐dependent (CDKs), Mitogen‐activated (MAPKs), Glycogen synthase (GSKs), dc2‐like (CLKs)] sterile (STE)‐MAPKs tyrosine (TK) kinase‐like (TKL) atypical other groups. Different families stimulate or inhibit others, forming intricate molecular network. This takes newly new PKIs as breakthrough point, aiming to clarify network relationship each pathway, well roles intervention, provide direction future drug development.
Language: Английский
Citations
67
Drug Discovery Today, Journal Year: 2023, Volume and Issue: 29(1), P. 103845 - 103845
Published: Nov. 26, 2023
Language: Английский
Citations
26
MedComm, Journal Year: 2023, Volume and Issue: 4(5)
Published: Oct. 1, 2023
Abstract Double‐strand break (DSB), a significant DNA damage brought on by ionizing radiation, acts as an initiating signal in tumor radiotherapy, causing cancer cells death. The two primary pathways for DSB repair mammalian are nonhomologous end joining (NHEJ) and homologous recombination (HR), which cooperate compete with one another to achieve effective repair. mechanism depends numerous regulatory variables. recognition the recruitment of components, instance, depend MRE11–RAD50–NBS1 (MRN) complex Ku70/80 heterodimer/DNA–PKcs (DNA–PK) complex, whose control is crucial determining pathway choice efficiency HR NHEJ. In‐depth elucidation pathway's molecular mechanisms has greatly facilitated creation proteins or pathways‐specific inhibitors advance precise therapy boost effectiveness radiotherapy. architectures, roles, processes, target reviewed this article. strategy application also discussed based advancement targeted response proteins.
Language: Английский
Citations
21
Nature Structural & Molecular Biology, Journal Year: 2023, Volume and Issue: 30(2), P. 140 - 147
Published: Jan. 5, 2023
Abstract DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA damage response repair. Using DNA-PK-selective inhibitor (M3814), we identified from one dataset two cryo-EM structures of in different states, intermediate state active state. Here show that activation regulated through conformational changes caused by binding ligand string region (residues 802–846) subunit, particularly helix-hairpin-helix motif 816–836) interacts DNA. These observations demonstrate regulatory role explain why dependent. Cooperation coordination among partners, disordered flexible regions mechanically HEAT repeats modulate kinase. Together previous findings, these results provide better molecular understanding catalysis.
Language: Английский
Citations
18
Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)
Published: March 11, 2024
Abstract We present a hydrogen/deuterium exchange workflow coupled to tandem mass spectrometry (HX-MS 2 ) that supports the acquisition of peptide fragment ions alongside their precursors. The approach enables true auto-curation HX data by mining rich set deuterated fragments, generated collisional-induced dissociation (CID), simultaneously confirm ID and authenticate MS 1 -based deuteration calculations. high redundancy provided fragments confidence assessment deuterium calculations using combinatorial strategy. requires data-independent (DIA) methods are available on most platforms, making switch HX-MS straightforward. Importantly, we find HX-DIA proteomics-grade wide-spread applications. Considerable time is saved through complex samples can now be characterized at higher throughput. illustrate these advantages in drug binding analysis ultra-large protein kinase DNA-PKcs, isolated directly from mammalian cells.
Language: Английский
Citations
8
International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(8), P. 4264 - 4264
Published: April 12, 2022
DNA double-strand break (DSB) is considered the most deleterious type of damage, which generated by ionizing radiation (IR) and a subset anticancer drugs. DNA-dependent protein kinase (DNA-PK), composed DNA-PK catalytic subunit (DNA-PKcs) Ku80-Ku70 heterodimer, acts as molecular sensor for DSB plays pivotal role in repair through non-homologous end joining (NHEJ). Cells deficient DNA-PKcs show hypersensitivity to IR several DNA-damaging agents. Cellular sensitivity agents can be augmented inhibition DNA-PK. A number small molecules that inhibit have been developed. Here, development evolution inhibitors targeting cancer therapy reviewed. Significant parts were developed based on structural similarity phosphatidylinositol 3-kinases (PI3Ks) PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some inhibitors, e.g., NU7026 NU7441, used extensively studies cellular function Recently M3814 AZD7648, are clinical trials way utilized combination with radiotherapy chemotherapy.
Language: Английский
Citations
23
Nucleic Acids Research, Journal Year: 2022, Volume and Issue: 50(13), P. 7697 - 7720
Published: July 8, 2022
Abstract Artemis nuclease and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are key components in nonhomologous DNA end joining (NHEJ), the major repair mechanism for double-strand breaks. activation by DNA-PKcs resolves hairpin ends formed during V(D)J recombination. deficiency disrupts development of adaptive immunity leads to radiosensitive T- B- severe combined immunodeficiency (RS-SCID). An activated state complex with DNA-PK was solved cryo-EM recently, which showed bound DNA. Here, we report that pre-activated form (basal state) Artemis:DNA-PKcs is stable on an agarose-acrylamide gel system, suitable structural analysis. Structures show domain dynamically positioned externally prior ABCDE autophosphorylation how both regulatory domains interact N-HEAT FAT DNA-PKcs. We define a mutually exclusive binding site XRCC4 peptide complex. All findings useful explaining hypomorphic L3062R missense mutation could lead insufficient activation, hence RS-SCID. Our results provide various target candidates design disruptors formation.
Language: Английский
Citations
23
Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(13), P. 6770 - 6783
Published: June 13, 2023
Ataxia-telangiectasia mutated (ATM) drives the DNA damage response via modulation of multiple signal transduction and repair pathways. Previously, ATM activity was implicated in promoting non-homologous end joining (NHEJ) pathway to a subset double-stranded breaks (DSBs), but how performs this function is still unclear. In study, we identified that phosphorylates DNA-dependent protein kinase catalytic subunit (DNA-PKcs), core NHEJ factor, at its extreme C-terminus threonine 4102 (T4102) DSBs. Ablating phosphorylation T4102 attenuates DNA-PKcs destabilizes interaction between Ku-DNA complex, resulting decreased assembly stabilization machinery Phosphorylation promotes NHEJ, radioresistance, increases genomic stability following DSB induction. Collectively, these findings establish key role for NHEJ-dependent DSBs through positive regulation DNA-PKcs.
Language: Английский
Citations
14
Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(9), P. 5048 - 5066
Published: Feb. 27, 2024
Two DNA repair pathways, non-homologous end joining (NHEJ) and alternative (A-EJ), are involved in V(D)J recombination chromosome translocation. Previous studies reported distinct mechanisms for translocation, with NHEJ humans A-EJ mice predominantly. depends on DNA-PKcs, a critical partner synapsis formation downstream component activation. While DNA-PKcs inhibition promotes translocations harboring microhomologies mice, its synonymous effect is not known. We find partial human cells leads to increased the continued involvement of dampened NHEJ. In contrast, complete substantially microhomology-mediated (MMEJ), thus bridging two different translocation between mice. Similar previous study Ku70 deletion, deletion G1/G0-phase mouse progenitor B cell lines, significantly impairs generated higher rates as consequence dysregulated coding signal joining. Genetic suppresses entirely, phenotypically resembling Ku70-deficient A-EJ. we necessary generating near-exclusive MMEJ associated Lig4 deficiency. Our underscores suppressing illegitimate rearrangement while also contributing both species.
Language: Английский
Citations
5
npj Precision Oncology, Journal Year: 2024, Volume and Issue: 8(1)
Published: July 23, 2024
Abstract The canonical role of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) in repairing DNA double-strand breaks combined with its reported dysregulation several malignancies has driven development DNA-PKcs inhibitors as therapeutics. However, until recently relationship between and tumorigenesis been primarily investigated regard to non-homologous end joining (NHEJ) repair. Emerging research uncovered non-canonical functions involved transcriptional regulation, telomere maintenance, metabolic immune signaling all which may also impinge on tumorigenesis. This review mainly discusses these roles cellular biology their potential contribution tumorigenesis, well evaluating implications targeting for cancer therapy.
Language: Английский
Citations
5