Olaparib for Metastatic Castration-Resistant Prostate Cancer

New England Journal of Medicine, Journal Year: 2020, Volume and Issue: 382(22), P. 2091 - 2102

Published: April 28, 2020

Multiple loss-of-function alterations in genes that are involved DNA repair, including homologous recombination associated with response to poly(adenosine diphosphate–ribose) polymerase (PARP) inhibition patients prostate and other cancers.

Language: Английский

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ROS and the DNA damage response in cancer

Redox Biology, Journal Year: 2018, Volume and Issue: 25, P. 101084 - 101084

Published: Dec. 21, 2018

Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the response (DDR). There is unequivocal pre-clinical clinical evidence ROS influence genotoxic stress caused by chemotherapeutics agents ionizing radiation. Recent studies have provided mechanistic insight into how also cellular to therapy, especially in context Double Strand Breaks (DSBs). This has led evaluation modulating combination with therapy for cancer, mixed success so far. These point dependent outcomes modulator combinations Chemotherapy radiotherapy, indicating need additional research field. In this review, we discuss current knowledge on effect response, its relevance.

Language: Английский

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DNA double-strand break repair-pathway choice in somatic mammalian cells

Nature Reviews Molecular Cell Biology, Journal Year: 2019, Volume and Issue: 20(11), P. 698 - 714

Published: July 1, 2019

Language: Английский

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DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: April 30, 2020

Abstract Radiotherapy is one of the most common countermeasures for treating a wide range tumors. However, radioresistance cancer cells still major limitation radiotherapy applications. Efforts are continuously ongoing to explore sensitizing targets and develop radiosensitizers improving outcomes radiotherapy. DNA double-strand breaks lethal lesions induced by ionizing radiation can trigger series cellular damage responses (DDRs), including those helping recover from injuries, such as activation sensing early transduction pathways, cell cycle arrest, repair. Obviously, these protective DDRs confer tumor radioresistance. Targeting DDR signaling pathways has become an attractive strategy overcoming radioresistance, some important advances breakthroughs have already been achieved in recent years. On basis comprehensively reviewing signal we provide update on novel promising druggable emerging that be exploited radiosensitization. We further discuss identified preclinical studies, current clinical trials, application chemical inhibitors targeting key proteins, DNA-PKcs (DNA-dependent protein kinase, catalytic subunit), ATM/ATR (ataxia–telangiectasia mutated Rad3-related), MRN (MRE11-RAD50-NBS1) complex, PARP (poly[ADP-ribose] polymerase) family, MDC1, Wee1, LIG4 (ligase IV), CDK1, BRCA1 (BRCA1 C terminal), CHK1, HIF-1 (hypoxia-inducible factor-1). Challenges radiation-induced targeted therapy also discussed based achievements biological field

Language: Английский

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R-Loops as Cellular Regulators and Genomic Threats

Molecular Cell, Journal Year: 2019, Volume and Issue: 73(3), P. 398 - 411

Published: Feb. 1, 2019

Language: Английский

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DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 9, 2021

Abstract Genomic instability is the hallmark of various cancers with increasing accumulation DNA damage. The application radiotherapy and chemotherapy in cancer treatment typically based on this property cancers. However, adverse effects including normal tissues injury are also accompanied by chemotherapy. Targeted therapy has potential to suppress cells’ damage response through tailoring patients lacking specific functions. Obviously, understanding broader role repair became a basic attractive strategy for targeted therapy, particular, raising novel hypothesis or theory field basis previous scientists’ findings would be important future promising druggable emerging targets. In review, we first illustrate timeline steps roles promotion developed, then summarize mechanisms regarding associated highlighting proteins behind targeting that initiate functioning abnormally duo extrinsic harm environmental factors, also, baseline drift leads harmful intrinsic therapy. addition, clinical therapeutic drugs effects, as well scheme relative trials were intensive discussed. Based background, suggest two hypotheses, namely “environmental gear selection” describe pathway evolution, “DNA drift”, which may play magnified mediating during treatment. This new shed light provide much better more comprehensive holistic view promote development research direction overcoming strategies patients.

Language: Английский

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A Genetic Map of the Response to DNA Damage in Human Cells

Cell, Journal Year: 2020, Volume and Issue: 182(2), P. 481 - 496.e21

Published: July 1, 2020

Language: Английский

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Targeting DNA damage response pathways in cancer

Nature reviews. Cancer, Journal Year: 2022, Volume and Issue: 23(2), P. 78 - 94

Published: Dec. 5, 2022

Language: Английский

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The human papillomavirus replication cycle, and its links to cancer progression: a comprehensive review

Clinical Science, Journal Year: 2017, Volume and Issue: 131(17), P. 2201 - 2221

Published: Aug. 10, 2017

HPVs (human papillomaviruses) infect epithelial cells and their replication cycle is intimately linked to differentiation. There are over 200 different HPV genotypes identified date each displays a strict tissue specificity for infection. infection can result in range of benign lesions, example verrucas on the feet, common warts hands, or genital warts. infects dividing basal where its dsDNA episomal genome enters nuclei. Upon cell division, an infected daughter begins process keratinocyte differentiation that triggers tightly orchestrated pattern viral gene expression accomplish productive A subset mucosal-infective HPVs, so-called ‘high risk’ (HR) cause cervical disease, categorized as low high grade. Most individuals will experience transient HR-HPV during lifetime but these infections not progress clinically significant disease cancer because immune system eventually recognizes clears virus. Cancer progression due persistent with HR-HPV. >99.7% cancers women, oropharyngeal cancers, predominantly men. HPV16 (HR-HPV genotype 16) most prevalent worldwide major HPV-associated cancers. At molecular level, increased oncoproteins E6 E7, which activate cycle, inhibit apoptosis, allow accumulation DNA damage. This review aims describe life discuss roles proteins replication. Routes persistence also discussed.

Language: Английский

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Phase separation of 53 BP 1 determines liquid‐like behavior of DNA repair compartments

The EMBO Journal, Journal Year: 2019, Volume and Issue: 38(16)

Published: July 1, 2019

Article1 July 2019Open Access Transparent process Phase separation of 53BP1 determines liquid-like behavior DNA repair compartments Sinan Kilic orcid.org/0000-0001-5009-8884 Department Molecular Mechanisms Disease, University Zurich, Switzerland Search for more papers by this author Aleksandra Lezaja Cancer Biology PhD Program, Life Science Zurich Graduate School, Marco Gatti Eliana Bianco Jone Michelena Ralph Imhof Matthias Altmeyer Corresponding Author [email protected] orcid.org/0000-0003-3780-1170 Information Kilic1, Lezaja1,2, Gatti1, Bianco1,2,3, Michelena1, Imhof1 and *,1 1Department 2Cancer 3Present address: Institute Biochemistry, ETH *Corresponding author. Tel: + 41 44 63 55 491; E-mail: The EMBO Journal (2019)38:e101379https://doi.org/10.15252/embj.2018101379 See also: R Piccinno et al (August 2019) PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses to feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract damage response (DDR) generates transient concentrate proteins activate signaling factors. physicochemical properties these spatially confined their function remain poorly understood. Here, we establish, based on live cell microscopy CRISPR/Cas9-mediated endogenous protein tagging, that 53BP1-marked are dynamic, show droplet-like behavior, undergo frequent fusion fission events. assembly, but not upstream accumulation γH2AX MDC1, is highly sensitive changes in osmotic pressure, temperature, salt concentration disruption hydrophobic interactions. substantiated optoDroplet experiments, which further allowed dissection sequence elements cooperate light-induced clustering. Moreover, found tumor suppressor p53 be enriched within optoDroplets, conditions disrupt phase impair 53BP1-dependent induction diminish target gene expression. We thus suggest integrates localized recognition factor assembly with global p53-dependent activation fate decisions. Synopsis effector forms characteristic foci at breaks, here exhibit liquid self-compartmentalization important downstream suppressor. droplet fusions fissions. conferred 53BP1, uncoupled from detection γH2AX-MDC1 accumulation. break sites abolished concentration, or experiments indicate multivalency reveal required Disruption impairs p21 upon damage. Introduction Detection double-strand breaks (DSBs) faithful crucial avoid loss genetic information counter chromosome translocations genomic instability. Consequently, defects associated neurodegeneration, cancer, aging, instability hallmark most tumors (Jackson Bartek, 2009). DDR initiated ATM kinase, phosphorylates histone variant H2AX generate (Shiloh Ziv, 2013; Blackford Jackson, 2017). adaptor MDC1 binds assemble ubiquitin E3 ligases RNF8 RNF168 recruit (Jungmichel Stucki, 2010; Lukas al, 2011b; Polo 2011; Panier Boulton, 2014; Pellegrino Altmeyer, 2016; Schwertman Wilson Durocher, sizeable chromatin domains, scaffold effectors shield lesions against excessive nucleolytic digestion. Restrained resection achieved recruitment RIF1, REV7, Shieldin complex (Dev 2018; Findlay Ghezraoui Gupta Mirman Noordermeer Setiaputra 2019). Additionally, promotes cycle checkpoint (DiTullio 2002; Fernandez-Capetillo Wang Brummelkamp 2006; Cuella-Martin 2016). How local why such multilayered multi-protein safeguard genome stability well Liquid–liquid has recently emerged as mechanism dynamically sub-divide intracellular space (Hyman Alberti, 2017; Banani Shin Brangwynne, relies multivalent weak interactions, often through intrinsically disordered sequences. Such interactions retain larger conformational flexibility compared complementary domain surfaces induced fit (Aguzzi Boeynaems 2018). Besides nucleolus, nuclear speckles, RNA granules, also silent heterochromatin domains were shown separate nucleus (Larson Strom occurs promoters super-enhancers (Boehning Boija Lu Sabari To extent other rely spatio-temporal confinement biological functions matter intense investigation. Although key signals defined, can events indicating hierarchical cascade allows regulation intermediate levels. For instance, precluded during mitosis, when CDK activity high chromosomes heavily condensed, even though unaffected (Giunta Orthwein 2014). Conversely, recruitments under deregulated (Gudjonsson 2012; Lukas, 2013a,b). Impaired turnover leads greatly enlarged compartments, occupy territories several square-micrometers, reaching far beyond γH2AX/MDC1 2012). These findings raise possibility that, despite recruitment, into may differ they prompted us investigate assemblies how affect functions. Results Multivalent underlying pH, pressure. In order assess would react osmolarity, monitored ionizing radiation (IR) quantitative image-based cytometry (QIBC), high-content approach resolved profiling (Altmeyer Toledo Ochs As observed previously, measured strong IR-induced increase G1, gradually declined S-phase increasing amounts replicated promote DSB homologous recombination (Chapman Saredi 2017), rose again late G2 (Fig 1A). Consistent prior work 2014), was blocked condensed mitosis 1B). Sorbitol-induced stress expectedly resulted rapid formation cytoplasmic granules (Appendix Fig S1A–C). Strikingly, however, sorbitol addition completely 1C Appendix S1D). sorbitol-induced suppression comparable siRNA-mediated depletion 53BP1-regulator S1E F) entailed complete abrogation RIF1 1D). Similarly, sucrose elevated concentrations mitigated S2A B). Live using GFP-53BP1 cells confirmed severely impaired disassembled preformed bodies spontaneous S2C). very similar effects non-transformed human epithelial RPE-1 canine MDCK S3A challenge-induced inhibition fully reversible quickly restored removed after S3C D). Surprisingly, neither nor lost ability accumulate around DSBs presence stress, suggesting osmosensitivity specific compartment EV1A Furthermore, different formation, temperature EV1C D), sensitivity EV1E F). Figure 1. hyperosmotic Asynchronously growing U-2 OS treated 0.5 Gy IR, recover indicated time periods, stained content quantification individual QIBC. Representative images QIBC analysis (A). Scale bars, 10 μm. Cells IR absence 0.4 M sorbitol, fixed 1 h later, analyzed Treatments (C); Download figure PowerPoint Click expand figure. EV1. Compartment disassembly change, irradiated quantified Gy, exposed recovery, same (C), NaCl (0, 100, 125, 150, 175 mM), later (E), While initial essential ensuing low, sub-lethal doses neocarzinostatin (NCS) than 2A S4A–D). Indeed, had disappeared 2–4 induction, whereas bright clearly visible time-points 2A). stably expressing either GFP-MDC1 nature long-lived 2B). consistent previous describing clustering (Aten 2004; Krawczyk Neumaier Roukos Aymard Sollazzo 2018), signs coalescence over 3A). Comparing intensity area suggested pronounced 3A B, S5A). time-lapse damage-induced showed underwent occasional 3C, S5B C). aliphatic alcohol 1,6-hexanediol, disrupts favorable liquid–liquid (Molliex 2015; Wegmann S5D E). Next, light dependency exclude potential bias ectopic expression, employed CRISPR/Cas9 engineer locus integrate an in-frame encoding small monomeric red fluorescent mScarlet S6A resulting could visualized fluorescence S6C), did S6D), γH2AX-positive S6E), typical cycle-regulated pattern S6F), siRNA treatment targeted S6G). our results, short challenge led 53BP1-mScarlet without affecting S6H I). More importantly, endogenously tagged expressed its native promoter assemblies, spherical shape, fissions 3D Movie EV1). 2. intensities plotted intensities, representative shown. 15-min intervals. provided, kinetics dissolution single-cell tracks. Bold lines represent averages n = 29 18 cells. Data information: 3. time-points. Mean 1,500 per time-point. (solid line) standard deviation mean (dashed lines) indicated. (A) intensity. 25 ng/ml NCS induce imaged 30-min Examples (green arrowheads magnified regions) (blue 53BP1-RFP cells, been engineered express natural promoter, (25 ng/ml) left higher magnification right. untreated, APH (0.5 μM) ATRi (1 replication stress-associated heritable lesions, (C–E) clastogen-induced assembles stress-induced inherited (Harrigan 2011a). bodies, occurring spontaneously enhanced frequency mild low-dose aphidicolin (APH) ATR inhibitor (ATRi) treatment, well, 3E). Finally, low levels 2 S4), dual labeling typically occurred discernible S6J). Taken together, conclude features separation. directly test whether possesses capacity separate, turned system mCherry-labeled Arabidopsis photoreceptor cryptochrome (Cry2) measure living (Taslimi before, amino-terminal prion-like FUS, established model (Shin 2017, 2018) oligomerization-prone Cry2 E490G mutant negative wild-type control EV2A). A Cry2-53BP1 fusion, rapid, 4A top panel, EV2B additional examples, EV2). Introducing single amino acid exchange (W1495A) tandem tudor (TTD) abrogate potentially confounding TTD (Drane intrinsic middle panel EV3). Different Cry2-MDC1 considerable bottom EV4), construct functional efficiently accumulated EV2C). noticed pH shift 7.4 5.5 rapidly FUS EV2D) formed optoDroplets acidic EV2E). Similar readily observed, demonstrating 4B). EV2. Cry2-mCherry-fusion constructs transfected activated blue light, followed 15-s OptoDroplets before (pre) 6 min (post) 100–250 condition 3 independent Additional examples full-length Cry2-mCherry-53BP1 activation. Cry2-mCherry-MDC1 ng/ml), γH2AX. HCl-adjusted medium 5.5, 5 later. Red bars part Cry2-mCherry fusion. 4. separates Light-induced Cry2-mCherry-53BP1, W1495A, Cry2-mCherry-MDC1. Quantifications 2–3 W1495A 15 s resolution. Fusing highlighted green insets. constructs. quantifications generated series deletion mutants identify driving This revealed C-terminus, comprising acids 1140–1972, sufficient oligomerization (OD) critically involved (Figs 4C EV2F). Interestingly, largely unstructured N-terminus dispensable stretches alone good predictor Recent FET (FUS, EWSR1, TAF15) family identified between tyrosines (Y) arginines (R) (Wang C-terminus S7A), providing explanation preferential region. OD inside yet abrogated responsiveness 4C). When combined toward light-inducible positive contribution C-terminal BRCT 4C), whose NHEJ remained ambiguous (Morales 2003; Ward Kilkenny 2008; Lee Noon Bothmer Lottersberger Knobel Baldock Kleiner Multiple Y/R-rich seem self-assembly. focused analyses (aa 1203–1972 W1495A). Also construct, 5A), concentration-dependent 5B). support reversibility pH-induced buffer back neutral S7B) 1,6-hexanediol S7C). recovery photobleaching (FRAP) (IRIF) all kinetics, degree mobility EV3A–D). 5. self-assembles nucleation centers manner induction. Concentration-dependent exemplified two neighboring expression level. lowly (mClow) (mChigh) three Cry2-mEGFP-53BP1 FokI-induced seconds FokI where light-activated mark lesion mCherry EV3. FRAP foci, bleached nucleoplasm monitored. 1–2 h, (1203–1972 W1495A) droplets Between 12 20 each condition. vitro, purified condensation μm-sized Ficoll EV4A B), condensates co-assembled DSB-mimicking fluorescently labeled EV4C vivo, being multiple random regions S8A), region 5C S8B C), seeding-dependent self-assembly amplified accrual compartment. conclusions reached versus photo-oligomerizable (Bracha EV4. vitro Purified Ficoll. unlabeled version mixed 9:1 ratio, fo

Language: Английский

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