RESUMO
BACKGROUND: Ruxolitinib (RUX) is a JAK1/2 inhibitor approved for the therapy of myelofibrosis (MF) based on clinical trials including only intermediate2-high risk (INT2/HIGH) patients. However, RUX is commonly used in intermediate-1 (INT1) patients, with scarce information on responses and outcome. METHODS: The authors investigated the benefit of RUX in 1055 MF patients, included in the "RUX-MF" retrospective study. RESULTS: At baseline (BL), 595 (56.2%) patients were at INT1-risk according to DIPSS (PMF) or MYSEC-PM (SMF). The spleen was palpable at <5 cm, between 5 and 10 cm, and >10 cm below costal margin in 5.9%, 47.4%, and 39.7% of patients, respectively; 300 (54.1%) were highly symptomatic (total symptom score ≥20). High-molecular-risk (HMR) mutations (IDH1/2, ASXL-1, SRSF2, EZH2, U2AF1Q157) were detected in 77/167 patients. A total of 101 (19.2%) patients had ≥1 cytopenia (Hb < 10 g/dL: n.36; PLT <100 x 109/L: n = 43; white blood cells <4 x 109/L: n = 40). After 6 months on RUX, IWG-MRT-defined spleen and symptoms response rates were 26.8% and 67.9%, respectively. In univariate analysis, predictors of SR at 6 months were no HMR mutations odds ratio [OR], 2.0, p = .05], no cytopenia (OR, 2.10; p = .01), and blasts <1% (OR, 1.91; p = .01). In multivariate analysis, absence of HMR maintained a significant association (OR, 2.1 [1.12-3.76]; p = .01). CONCLUSIONS: In INT1 patients, responses were more frequent and durable, whereas toxicity rates were lower compared to INT2/high-risk patients. Presence of HMR mutations, cytopenia, and peripheral blasts identified less-responsive INT1 patients, who may benefit for alternative therapeutic strategies.
RESUMO
Deletions in mitochondrial DNA (mtDNA) are associated with diverse human pathologies including cancer, aging and mitochondrial disorders. Large-scale deletions span kilobases in length and the loss of these associated genes contributes to crippled oxidative phosphorylation and overall decline in mitochondrial fitness. There is not a united view for how mtDNA deletions are generated and the molecular mechanisms underlying this process are poorly understood. This review discusses the role of replication and repair in mtDNA deletion formation as well as nucleic acid motifs such as repeats, secondary structures, and DNA damage associated with deletion formation in the mitochondrial genome. We propose that while erroneous replication and repair can separately contribute to deletion formation, crosstalk between these pathways is also involved in generating deletions.
Assuntos
Reparo do DNA , Replicação do DNA , DNA Mitocondrial/biossíntese , Doenças Genéticas Inatas/genética , Mitocôndrias/genética , Doenças Mitocondriais/genética , Quebras de DNA de Cadeia Dupla , Reparo de Erro de Pareamento de DNA , DNA Mitocondrial/metabolismo , Doenças Genéticas Inatas/metabolismo , Humanos , Mitocôndrias/patologia , Doenças Mitocondriais/metabolismo , Fosforilação Oxidativa , Deleção de SequênciaRESUMO
Alternative splicing of terminal exons increases transcript and protein diversity. How physiological and pathological stimuli regulate the choice between alternative terminal exons is, however, largely unknown. Here, we show that Brahma (BRM), the ATPase subunit of the hSWI/SNF chromatin-remodeling complex interacts with BRCA1/BARD1, which ubiquitinates the 50 kDa subunit of the 3' end processing factor CstF. This results in the inhibition of transcript cleavage at the proximal poly(A) site and a shift towards inclusion of the distal terminal exon. Upon oxidative stress, BRM is depleted, cleavage inhibition is released, and inclusion of the proximal last exon is favoored. Our findings elucidate a novel regulatory mechanism, distinct from the modulation of transcription elongation by BRM that controls alternative splicing of internal exons.
Assuntos
Processamento Alternativo , Proteína BRCA1/metabolismo , Fator Estimulador de Clivagem/metabolismo , Éxons , Estresse Oxidativo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Adenosina Trifosfatases/metabolismo , Linhagem Celular Tumoral , Regulação da Expressão Gênica , Humanos , Complexos Multiproteicos , Estresse Oxidativo/genética , Poli A , Ligação Proteica , Fatores de Transcrição/genética , UbiquitinaçãoRESUMO
Cancer-associated fibroblasts (CAFs) are components of the tumor microenvironment and represent appealing therapeutic targets for translational studies. Conventional protein-based biomarkers for CAFs have been reported to be limited in their specificity, rendering difficult the identification of CAFs from normal fibroblasts (NFs) in clinical samples and dampening the development of CAF-targeted therapies to treat cancer. In this study, we propose the mitochondrial RNA and the mitochondrial DNA (mtDNA) common deletion (CD) as novel indicators of CAF identity. We found that cancer-activation correlated with decreased levels of the mtDNA CD, a condition not due to altered mitochondria count or cellular redox state, but potentially linked to the generalized overexpression of mtDNA maintenance genes in CAFs. Decreased mtDNA CD content in CAFs was associated with moderate to strong overexpression of mtDNA-encoded genes and to slightly improved mitochondrial function. We identified similar patterns of upregulation of mtDNA-encoded genes in independent single-cell RNA seq data obtained from squamous cell carcinoma (SCC) patients. By using the identified nucleic acids-based indicators, identification of CAFs from NFs could be improved, leading to potential therapeutic benefits in advancing translational and clinical studies.
Assuntos
Fibroblastos Associados a Câncer , Carcinoma de Células Escamosas , Humanos , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/patologia , Fibroblastos/patologia , Pele/patologia , DNA Mitocondrial/genética , Microambiente Tumoral/genéticaRESUMO
This paper reports the synthesis of a series of evodiamine derivatives. We assayed the ability to inhibit cell growth on three human tumour cell lines (H460, MCF-7 and HepG2) and we evaluated the capacity to interfere with the catalytic activity of topoisomerase I both by the relaxation assay and the occurrence of the cleavable complex. Moreover, whose effect on sirtuins 1, 2 and 3 was investigated. Finally, molecular docking analyses were performed in an attempt to rationalize the biological results.
Assuntos
DNA Topoisomerases Tipo I/química , Quinazolinas/química , Sirtuínas/antagonistas & inibidores , Inibidores da Topoisomerase I/química , Alcaloides/química , Sítios de Ligação , Carbolinas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Ativação Enzimática/efeitos dos fármacos , Células Hep G2 , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinas/síntese química , Quinazolinas/farmacologia , Sirtuínas/metabolismo , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/farmacologiaRESUMO
Mitochondrial DNA (mtDNA) mutations are found in several human pathologies and are associated with aging. Deletion mutations in mtDNA result in the loss of essential genes for mitochondrial function. Over 250 deletion mutations have been reported and the common deletion is the most frequent mtDNA deletion linked to disease. This deletion removes 4977 base pairs of mtDNA. It has previously been shown that exposure to UVA radiation can promote the formation of the common deletion. Furthermore, aberrations in mtDNA replication and repair are associated with formation of the common deletion. However, molecular mechanisms describing the formation of this deletion are poorly characterized. This chapter describes a method to irradiate human skin fibroblasts with physiological doses of UVA and the subsequent detection of the common deletion by quantitative PCR analysis.
Assuntos
DNA Mitocondrial , Mitocôndrias , Humanos , DNA Mitocondrial/genética , Deleção de Sequência , Mitocôndrias/genética , Envelhecimento/genética , MutaçãoRESUMO
Laccase-catalysed oxidation of ergot alkaloids in the absence of chemical mediators allowed the unexpected isolation of the mono-hydroxylated derivatives of compounds 2-7. Structure determination by NMR techniques clearly indicated that hydroxylation took place at the C-4 benzylic position. Quite notably, the proposed protocol allowed, for the first time, functionalisation at the C-4 position of the ergoline skeleton. Depending on the absence or on the presence of a C-10 α-methoxy substituent, hydroxylation was either stereoselective (furnishing C-4α OH derivatives) or gave rise to a C-4α/C-4ß OH mixture in a 2:1 ratio, respectively.
Assuntos
Alcaloides de Claviceps/química , Lacase/química , Catálise , Hidroxilação , Lacase/metabolismo , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , EstereoisomerismoRESUMO
Distinct cellular DNA damage repair pathways maintain the structural integrity of DNA and protect it from the mutagenic effects of genotoxic exposures and processes. The occurrence of O6-carboxymethylguanine (O6-CMG) has been linked to meat consumption and hypothesized to contribute to the development of colorectal cancer. However, the cellular fate of O6-CMG is poorly characterized and there is contradictory data in the literature as to how repair pathways may protect cells from O6-CMG mutagenicity. To better address how cells detect and remove O6-CMG, we evaluated the role of two DNA repair pathways in counteracting the accumulation and toxic effects of O6-CMG. We found that cells deficient in either the direct repair protein O6-methylguanine-DNA methyltransferase (MGMT), or key components of the nucleotide excision repair (NER) pathway, accumulate higher levels O6-CMG DNA adducts than wild type cells. Furthermore, repair-deficient cells were more sensitive to carboxymethylating agents and displayed an increased mutation rate. These findings suggest that a combination of direct repair and NER circumvent the effects O6-CMG DNA damage.
Assuntos
Reparo do DNA , Mutagênicos , DNA/química , Adutos de DNA , Dano ao DNA , Mutagênese , O(6)-Metilguanina-DNA Metiltransferase/genética , O(6)-Metilguanina-DNA Metiltransferase/metabolismoRESUMO
A very efficient three-component synthesis of a series of syn α-hydroxy-ß-amino esters, obtained in high diastereoselection and yield, was realized starting from an aldehyde, benzylamine, and the ketene silyl acetals derived from Ley's lactones. The synthetic protocol was optimized and the above compounds were obtained without the isolation of intermediates. The origin of the observed diastereoselection was investigated through a computational model of the key reaction step.
Assuntos
Aminoácidos/química , Aminoácidos/síntese química , Ácidos de Lewis/química , Aldeídos/química , Aminas/química , Catálise , Etilenos/química , Cetonas/química , Modelos Moleculares , Conformação Molecular , Estereoisomerismo , Especificidade por SubstratoRESUMO
The naturally occurring coumarins and resveratrol, attract great attention due to their wide range of biological properties, including anticancer, antileukemic, antibacterial and anti-inflammatory activities; moreover, their cancer chemopreventive property have been recently emphasized. A novel class of hybrid compounds, obtained by introducing a substituted trans-vinylbenzene moiety on a coumarin backbone, was synthesized and evaluated for the antitumor profile. A number of derivatives showed a good antiproliferative activity, in some cases higher to that of the reference compound resveratrol. The most promising compounds in this series were 14 and 17, endowed with excellent antiproliferative and proapoptotic activities. The present study suggests that the 7-methoxycoumarin nucleus, together with the 3,5-disubstitution pattern of the trans-vinylbenzene moiety, are likely promising structural features to obtain excellent antitumor compounds endowed with a apoptosis-inducing capability.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Estilbenos/farmacologia , Anticarcinógenos , Antineoplásicos/química , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes , Linhagem Celular Tumoral , Quimera , Cumarínicos/química , Cumarínicos/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Óxidos/farmacologia , Resveratrol , Estilbenos/química , Relação Estrutura-AtividadeRESUMO
The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC(50) values ranging from 0.03 to 12.2 µM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.
Assuntos
Antineoplásicos/síntese química , DNA Topoisomerases Tipo I/efeitos dos fármacos , Inibidores da Topoisomerase I/síntese química , Inibidores da Angiogênese , Animais , Camptotecina/análogos & derivados , Camptotecina/síntese química , Camptotecina/farmacologia , Caspases/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Espécies Reativas de Oxigênio , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/químicaRESUMO
Novel C-seco-taxoids were synthesized from 10-deacetylbaccatin III and their potencies evaluated against drug-sensitive and drug-resistant cancer cell lines. The drug-resistant cell lines include ovarian cancer cell lines resistant to cisplatin, topotecan, adriamycin and paclitaxel overexpressing class III beta-tubulin, A2780TC1 and A2780TC3. The last two cell lines were selected through chronic exposure of A2780wt to paclitaxel and Pgp blocker cyclosporine. All novel C-seco-taxoids exhibited remarkable potency against A2780TC1 and A2780TC3 cell lines, and no cross resistance to cisplatin- and topotecan-resistant cell lines, A2780CIS and A2780TOP. Four of those C-seco-taxoids exhibit much higher activities than IDN5390 against paclitaxel-resistant cell lines, A2780ADR, A2780TC1 and A2780TC3. SB-CST-10202 possesses the best all-round high potencies across different drug-resistant cell lines. Molecular modeling studies, including molecular dynamics simulations, on the drug-protein complexes of class I and III beta-tubulins were performed to identify possible cause of the remarkable potency of these C-seco-taxoids against paclitaxel-resistant cell lines overexpressing class III beta-tubulin.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Paclitaxel/farmacologia , Taxoides/química , Taxoides/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Feminino , Humanos , Modelos Moleculares , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Tubulina (Proteína)/genéticaRESUMO
DNA double-strand breaks (DSBs) disrupt the structural integrity of chromosomes. Proper DSB repair pathway choice is critical to avoid the type of gross chromosomal rearrangements that characterize cancer cells. Recent findings reveal S-fatty acylation and membrane anchorage of Rap1-interacting factor 1 (Rif1) as a mechanism providing spatial control over DSB repair pathway choice.
RESUMO
Rif1 is involved in telomere homeostasis, DNA replication timing, and DNA double-strand break (DSB) repair pathway choice from yeast to human. The molecular mechanisms that enable Rif1 to fulfill its diverse roles remain to be determined. Here, we demonstrate that Rif1 is S-acylated within its conserved N-terminal domain at cysteine residues C466 and C473 by the DHHC family palmitoyl acyltransferase Pfa4. Rif1 S-acylation facilitates the accumulation of Rif1 at DSBs, the attenuation of DNA end-resection, and DSB repair by non-homologous end-joining (NHEJ). These findings identify S-acylation as a posttranslational modification regulating DNA repair. S-acylated Rif1 mounts a localized DNA-damage response proximal to the inner nuclear membrane, revealing a mechanism of compartmentalized DSB repair pathway choice by sequestration of a fatty acylated repair factor at the inner nuclear membrane.
Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Proteínas Repressoras/genética , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética , Acilação , Reparo do DNA , Membrana Nuclear/metabolismo , Proteínas Repressoras/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ligação a Telômeros/metabolismoRESUMO
The synthesis and the X-ray structure of 16a-thiocamptothecin (TCPT), the thiopyridone analog of camptothecin (CPT), are accomplished. The crystal contains two structurally identical, yet independent molecules. Both of them are connected to other molecules via two intermolecular hydrogen bonds. S-methylation of TCPT leads to the cleavage of the C-ring. The cytotoxic activity of TCPT was evaluated against different human tumor cell lines using CPT as reference compound.
Assuntos
Antineoplásicos/síntese química , Camptotecina/análogos & derivados , Tionas/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/síntese química , Camptotecina/química , Camptotecina/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Dano ao DNA , DNA Topoisomerases Tipo I/química , Humanos , Modelos Moleculares , Tionas/química , Tionas/farmacologiaRESUMO
A series of camptothecin open-ring lactone tripartate conjugates were synthesized, in which polyamine side chains with different architecture (ethane-1,2-diamine, spermidine, homospermidine, spermine, and 4,8,13,17-tetraza-icosane-1,20-diamine) are linked to the 21-carboxylic function through an amidic bond, while the 17-CH(2)OH is acetylated. The rationale for the synthesis of these compounds was to explore the influence of the polyamine architecture on the activity of these CPT conjugates into cells, since the positively charged ammonium cations would favor interaction through electrostatic binding to the negatively charged DNA backbone. Topoisomerase I-mediated DNA cleavage assay was used to investigate the ability of these compounds to stimulate the DNA damage. The cleavage pattern was found to be similar to that of SN38 for all the new CPTs. The CPT tripartates were tested for growth inhibition ability against the human non-small-cell lung cancer carcinoma NCI-H460 cell line. Although these compounds were less potent than topotecan, SN38, and CPT after 1 h of treatment, the antiproliferative effects greatly increased after 72 h of exposure. The growth inhibition potency during long-term exposure is correlated with the number of charges of the 21-amide substituent. Both cleavage assay and in vitro effects support the interpretation that the compounds may have inhibitory activity also in the open-ring form. The architecture of the polyamine moiety is important for antiproliferative activity, and a balance between the hydrophilic and lipophilic properties of the polyamine is critical for CPT potency.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Camptotecina/química , Camptotecina/farmacologia , Lactonas/química , Poliaminas/química , Animais , Antineoplásicos/metabolismo , Camptotecina/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Clivagem do DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , Humanos , Fatores de TempoRESUMO
The synthesis of new D-seco-C-nor-taxane derivatives in which the D-ring has been deleted and the C-ring has been transformed into a new pentatomic ring, i.e., the polyfunctionalized tetrahydrofuranosyl and cyclopentenyl or cyclopentyl ring, was performed starting from baccatin III derivatives. The synthetic strategy adopted took advantage of the oxetane ring opening and disconnection of the C4-C5 bond, followed by an intramolecular condensation. The formation of furanosyl or cyclopentyl rings is strictly dependent on the presence of unprotected or protected oxygen at C-7 in the starting material. The reactions proceeded with good diastereoselectivity with control of the stereochemistry of one or two stereocenters.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Ciclopentanos/química , Furanos/química , Taxoides/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/toxicidade , Linhagem Celular , Estereoisomerismo , Taxoides/química , Taxoides/toxicidadeRESUMO
A series of novel hybrid compounds obtained by the attachment of anhydrovinblastine, vinorelbine, and vindoline to thiocolchicine, podophyllotoxin, and baccatin III are described. Two types of diacyl spacers are introduced. The influence of the hybrid compounds on tubulin polymerization is reported. The results highlight the importance of the length of the spacer. Immunofluorescence microscopy and flow cytometry measurements that compound with the best in vitro activity could disrupt microtubule networks in cell and prevent the formation of the proper spindle apparatus, thereby causing cell cycle arrest in the G2/M phase. The newly synthesized compounds were tested in the human lung cancer cell line A549.
Assuntos
Alcaloides/síntese química , Colchicina/análogos & derivados , Podofilotoxina/síntese química , Taxoides/síntese química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/metabolismo , Vimblastina/análogos & derivados , Vimblastina/síntese química , Alcaloides/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Colchicina/síntese química , Colchicina/toxicidade , Técnicas de Química Combinatória , Dimerização , Desenho de Fármacos , Humanos , Podofilotoxina/toxicidade , Radiossensibilizantes/síntese química , Radiossensibilizantes/toxicidade , Suínos , Taxoides/toxicidade , Moduladores de Tubulina/toxicidade , Vimblastina/toxicidade , VinorelbinaRESUMO
A series of water-soluble camptothecins obtained by linking a spermidine moiety to the 21-position of the open form through an amidic bond have been tested for their biochemical and biological activities. Growth inhibition assay on the human non-small cell lung cancer carcinoma NCI-H460 cell line revealed that the camptothecin analogues were less potent than topotecan and SN38 after 1 hour of treatment. The potency increased after 72 hours of exposure, being similar to that of reference camptothecins. The analysis of topoisomerase I-mediated DNA cleavage using the purified enzyme indicated that the novel camptothecin analogues retained ability to poison topoisomerase I and displayed the same cleavage pattern of SN38. Persistence of the DNA cleavage was comparable with that of SN38. Stabilization of the cleavable complex was not the result of hydrolysis of the N-C bond between polyamine and the drug because no free camptothecin was recovered at the end of DNA cleavage in presence of IDN5174, the analogue selected for detailed studies. IDN5174 exhibited an antitumor activity comparable with that of topotecan and irinotecan against NCI-H460 tumor xenograft. The pharmacokinetics in mice showed a favorable disposition in tumor tissue with low amount of camptothecin detectable in plasma and tumor (around 5-10%), thus supporting the efficacy of intact IDN5174. In conclusion, we found that IDN5174 maintained the biological and antitumor properties, in spite of lack of the closed E ring. The available results support the interpretation that the polyamine linked at the 21-position may allow a favorable drug interaction in the ternary complex.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/análogos & derivados , Animais , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/farmacocinética , Camptotecina/farmacologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , DNA Topoisomerases Tipo I/metabolismo , Humanos , Lactonas/farmacocinética , Lactonas/farmacologia , Camundongos , Espermidina/análogos & derivados , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cells have evolved conserved mechanisms to protect DNA ends, such as those at the termini of linear chromosomes, or those at DNA double-strand breaks (DSBs). In eukaryotes, DNA ends at chromosomal termini are packaged into proteinaceous structures called telomeres. Telomeres protect chromosome ends from erosion, inadvertent activation of the cellular DNA damage response (DDR), and telomere fusion. In contrast, cells must respond to damage-induced DNA ends at DSBs by harnessing the DDR to restore chromosome integrity, avoiding genome instability and disease. Intriguingly, Rif1 (Rap1-interacting factor 1) has been implicated in telomere homeostasis as well as DSB repair. The protein was first identified in Saccharomyces cerevisiae as being part of the proteinaceous telosome. In mammals, RIF1 is not associated with intact telomeres, but was found at chromosome breaks, where RIF1 has emerged as a key mediator of pathway choice between the two evolutionary conserved DSB repair pathways of non-homologous end-joining (NHEJ) and homologous recombination (HR). While this functional dichotomy has long been a puzzle, recent findings link yeast Rif1 not only to telomeres, but also to DSB repair, and mechanistic parallels likely exist. In this review, we will provide an overview of the actions of Rif1 at DNA ends and explore how exclusion of end-processing factors might be the underlying principle allowing Rif1 to fulfill diverse biological roles at telomeres and chromosome breaks.