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| Open AccessPof8 is a La-related protein and a constitutive component of telomerase in fission yeast
The core of the telomerase holoenzyme is composed of the reverse transcriptase and the non-coding RNA template. Here the authors identify Pof8 as a new constitutive component of fission yeast telomerase, loss of which causes telomerase assembly defects and critically short telomeres.
- Diego J. Páez-Moscoso
- , Lili Pan
- & Peter Baumann
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Article
| Open AccessLARP7 family proteins have conserved function in telomerase assembly
The telomerase holoenzyme is minimally composed of the reverse transcriptase and the RNA template. Here the authors identify Lar7 as a member of the full complex that helps to stabilise it and protect telomerase RNA from degradation.
- Laura C. Collopy
- , Tracy L. Ware
- & Kazunori Tomita
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Article
| Open AccessSub-kb Hi-C in D. melanogaster reveals conserved characteristics of TADs between insect and mammalian cells
Topologically associating domain (TAD) boundaries in flies seem to be different from those in mammals. Here, the authors use Hi-C with sub-kb resolution to identify about 4000 TADs in flies, most demarcated by the insulator complexes BEAF-32/CP190 or BEAF-32/Chromator like CTCF/cohesin in mammals.
- Qi Wang
- , Qiu Sun
- & Zhifeng Shao
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Article
| Open AccessCTCF driven TERRA transcription facilitates completion of telomere DNA replication
TERRA RNA is involved in maintaining stability during telomere repeat replication. Here the authors, by using CRISPR/Cas9, mutate CTCF-binding sites at start site of TERRA transcripts and find that subtelomeric CTCF facilitates telomeric DNA replication by promoting TERRA transcription.
- Kate Beishline
- , Olga Vladimirova
- & Paul M. Lieberman
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Article
| Open AccessBactofilin-mediated organization of the ParABS chromosome segregation system in Myxococcus xanthus
The roles played by bactofilins, a widespread type of bacterial cytoskeletal elements, are unclear. Here, the authors show that the bactofilins BacNOP facilitate proper subcellular localization of the ParABS chromosome segregation system in the model organism Myxococcus xanthus.
- Lin Lin
- , Manuel Osorio Valeriano
- & Martin Thanbichler
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Article
| Open AccessEroded telomeres are rearranged in quiescent fission yeast cells through duplications of subtelomeric sequences
How both telomere stability is regulated and dysfunctional telomeres processed in quiescent cells is poorly understood. Here, the authors provide evidence that eroded telomeres in quiescent fission yeast are rearranged by homologous recombination through duplications of subtelomeric sequences.
- Laetitia Maestroni
- , Julien Audry
- & Stéphane Coulon
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Article
| Open AccessA method for measuring the distribution of the shortest telomeres in cells and tissues
Short telomeres are a hallmark of senescence and can result in genomic instability as well as cancer progression. Here, the authors present TeSLA, a technique to accurately detect telomeres under 1 kb in length.
- Tsung-Po Lai
- , Ning Zhang
- & Jerry W. Shay
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Article
| Open AccessModulation of telomere protection by the PI3K/AKT pathway
Regulation of telomeres and the insulin/PI3K pathway both have roles in aging and cancer development but have not been functionally linked. Here the authors demonstrate that PI3K, via downstream targets, regulates TRF1 via phosphorylation.
- Marinela Méndez-Pertuz
- , Paula Martínez
- & Maria A. Blasco
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Article
| Open AccessReconstitution of human shelterin complexes reveals unexpected stoichiometry and dual pathways to enhance telomerase processivity
The human shelterin complex protects telomere ends from being recognized as damaged DNA sites and regulates telomere length in conjunction with telomerase. Here the authors establish the stoichiometries of human shelterin complexes of various compositions and show shelterin provides dual pathways to stimulate telomerase processivity.
- Ci Ji Lim
- , Arthur J. Zaug
- & Thomas R. Cech
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Article
| Open AccessThe Ino80 complex mediates epigenetic centromere propagation via active removal of histone H3
The histone variant CENP-A marks active centromeres and replaces H3 at centromeres through a poorly understood mechanism. Here, the authors provide evidence that the chromatin remodeller Ino80 promotes CENP-A chromatin assembly at the centromere in fission yeast.
- Eun Shik Choi
- , Youngseo Cheon
- & Daeyoup Lee
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Article
| Open AccessTDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription
DNA double-strand breaks (DSBs) induced by topoisomerase II (TOP2) are rejoined by TDP2-dependent non-homologous end-joining (NHEJ) but whether this promotes or suppresses translocations is not clear. Here the authors show that TDP2 suppresses chromosome translocations from DSBs introduced during gene transcription.
- Fernando Gómez-Herreros
- , Guido Zagnoli-Vieira
- & Keith W. Caldecott
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Article
| Open AccessCentromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition
Centromere maintenance depends on the persistence of the histone variant CENP-A at the centromeres. Here, the authors characterize the core centromeric nucleosome complex wherein CENP-C confers a stable CENP-A nucleosome conformation and CENP-N fastens CENP-A to the DNA.
- Lucie Y. Guo
- , Praveen Kumar Allu
- & Ben E. Black
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Article
| Open AccessInner centromere localization of the CPC maintains centromere cohesion and allows mitotic checkpoint silencing
Precise chromosome segregation during mitosis requires coordination of stable chromosome bi-orientation with anaphase onset, however the underlying mechanism is not clear. Here the authors show that inner centromere localization of the chromosomal passenger complex maintains centromeric cohesion on bi-oriented chromosomes and allows mitotic checkpoint silencing.
- Rutger C. C. Hengeveld
- , Martijn J. M. Vromans
- & Susanne M. A. Lens
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Article
| Open AccessMaternal age-dependent APC/C-mediated decrease in securin causes premature sister chromatid separation in meiosis II
Sister chromatid cohesion during meiosis II (MII), maintained by securin-mediated inhibition of separase, is reduced in aged mouse oocytes. Here the authors show that, in MII oocytes, securin levels are reduced by increased destruction by the anaphase promoting complex/cyclosome.
- Ibtissem Nabti
- , Rosanna Grimes
- & John Carroll
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Article
| Open AccessStructural and functional analysis of the human POT1-TPP1 telomeric complex
POT1 and TTP1 are part of the shelterin complex that caps and stabilizes the ends of telomeres. Here the authors present a structural analysis of the human POT1-TTP1 complex, shedding light on how it assembles and how cancer-associated mutations impact its assembly and function.
- Cory Rice
- , Prashanth Krishna Shastrula
- & Emmanuel Skordalakes
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Article
| Open AccessStructural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer
Human telomeres are protected by a specialized shelterin complex composed of six proteins. Here the authors structurally characterize the interaction between the POT1-TPP1 shelterin component and identify mutations associated with genome instability and cancer that disrupt the POT1-TPP1 interaction.
- Cong Chen
- , Peili Gu
- & Ming Lei
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Article
| Open AccessMutual reinforcement between telomere capping and canonical Wnt signalling in the intestinal stem cell niche
Mice lacking telomerase provide a model to study pathogenesis caused by critical telomere shortening. Here, the authors provide evidence that telomere shortening causes downregulation of Wnt signalling in intestinal crypts and that defects can be partially rescued by treatment with Wnt agonists.
- Ting-Lin B. Yang
- , Qijun Chen
- & F. Brad Johnson
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Article
| Open AccessDefined chromosome structure in the genome-reduced bacterium Mycoplasma pneumoniae
The three-dimensional architecture of genome-reduced bacteria is poorly understood. Here the authors combine Hi-C with super-resolution microscopy inMycoplasma pneumoniaeand provide evidence of how supercoiling and local organization influences gene regulation.
- Marie Trussart
- , Eva Yus
- & Luís Serrano
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Article
| Open Accessα-amino trimethylation of CENP-A by NRMT is required for full recruitment of the centromere
Centromeres are chromosomal domains epigenetically specified by the presence of the CENP-A containing nucleosomes that control chromosome segregation. Here the authors show that α-amino trimethylation of CENP-A by the enzyme NRMT is required for centromere function, faithful chromosome segregation and cell survival.
- Kizhakke M. Sathyan
- , Daniele Fachinetti
- & Daniel R. Foltz
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Article
| Open AccessDNA damage response inhibition at dysfunctional telomeres by modulation of telomeric DNA damage response RNAs
The DNA damage response (DDR) involves site-specific small non-coding RNAs. Here the authors show that telomere dysfunction induces transcription of telomeric DNA damage response RNAs that are necessary for DDR activation, which can be specifically muted by antisense inhibitory oligonucleotides.
- Francesca Rossiello
- , Julio Aguado
- & Fabrizio d’Adda di Fagagna
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Article
| Open AccessSpecialized interfaces of Smc5/6 control hinge stability and DNA association
Structural Maintenance of Chromosomes (SMC) complexes maintain genome integrity by regulating the segregation of chromosomes. Here, Altet al. describe the structure of the heterodimeric Smc5/6-hinge from fission yeast and define functional features critical for Smc5/6’s cellular function.
- Aaron Alt
- , Hung Q. Dang
- & Antony W. Oliver
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Article
| Open AccessTelomeres in ICF syndrome cells are vulnerable to DNA damage due to elevated DNA:RNA hybrids
ICF syndrome cells exhibit shortened telomeres and elevated levels of the noncoding RNA TERRA. Here the authors show this is associated with high levels of DNA damage, suggesting an increase in telomere dysfunction due to the formation of DNA: RNA hybrids
- Shira Sagie
- , Shir Toubiana
- & Sara Selig
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Article
| Open AccessStructure of the cohesin loader Scc2
The cohesin complex maintains genome integrity by ensuring correct sister-chromatid segregation during mitosis and meiosis. Here, Chaoet al. present a pseudo-atomic model of the full-length Scc2–Scc4 cohesin loader complex and reveal key Scc2 surfaces crucial for cohesin loading.
- William C. H. Chao
- , Yasuto Murayama
- & Martin R. Singleton
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Article
| Open AccessEpigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance
Centromeres are centrochromatin domains with CENP-A and H3 nucleosomes carrying transcription-associated modifications. Here the authors target synthetic modules to the centromeres to show that transcription plus histone modifications are required for CENP-A assembly and centrochromatin maintenance.
- Oscar Molina
- , Giulia Vargiu
- & William C. Earnshaw
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Article
| Open AccessAcetylation of histone H4 lysine 5 and 12 is required for CENP-A deposition into centromeres
The deposition of histone H3 variant CENP-A bound with histone H4 is a key feature designating the centromere region of a chromosome. Here the authors show acetylation on residues K5 and K12 in histone H4, mediated by the RbAp46/48-Hat1 complex, is required for deposition of CENP-A-H4 into centromeres.
- Wei-Hao Shang
- , Tetsuya Hori
- & Tatsuo Fukagawa
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Article
| Open AccessC14ORF39/SIX6OS1 is a constituent of the synaptonemal complex and is essential for mouse fertility
The synaptonemal complex is a meiosis-specific proteinaceous structure that supports homologous chromosome pairs during meiosis. Here, the authors show that SIX6OS1 (of previously unknown function) is part of the synaptonemal complex central element and upon deletion in mice, causes defective chromosome synapsis and infertility.
- Laura Gómez-H
- , Natalia Felipe-Medina
- & Alberto M. Pendas
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Article
| Open AccessChromosome biorientation produces hundreds of piconewtons at a metazoan kinetochore
Chromosomes bind microtubules (MT) from opposite spindle poles and the generated tension stabilizes kinetochore-MT attachments. Here the authors measure kinetochore forces by engineering two force sensors and propose that kinetochore fibers exert hundreds of pNs of force to bioriented kinetochores.
- Anna A. Ye
- , Stuart Cane
- & Thomas J. Maresca
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Article
| Open AccessAntagonistic roles of Drosophila Tctp and Brahma in chromatin remodelling and stabilizing repeated sequences
Genome stability is important for normal cellular function. Here, Hong and Choi show that translationally controlled tumour protein (TCTP) in Drosophilaregulates pericentromeric chromatin remodelling and transcription via negatively regulating a chromatin remodeler Brahma.
- Sung-Tae Hong
- & Kwang-Wook Choi
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Article
| Open AccessTelomeric RNAs are essential to maintain telomeres
The telomeric long-non coding RNA, TERRA, has been proposed in the past to modulate different telomeric functions based on in vitrostudies. Here the authors show, using a genetic deletion approach, that TERRA is transcribed from the 20q subtelomere and that it is essential for telomere maintenance.
- Juan José Montero
- , Isabel López de Silanes
- & Maria A. Blasco
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Article
| Open AccessOrdered chromatin changes and human X chromosome reactivation by cell fusion-mediated pluripotent reprogramming
Reactivation of the inactive X chromosome (Xi) has modelled epigenetic reprogramming in mouse. Here, by using cell fusion between human female fibroblasts and mouse embryonic stem cells, the authors show a complex hierarchy of epigenetic changes that are required to reactivate the genes on the human Xi chromosome.
- Irene Cantone
- , Hakan Bagci
- & Amanda G. Fisher
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Article
| Open AccessPTEN regulates EG5 to control spindle architecture and chromosome congression during mitosis
One of the cellular functions of the tumour suppressor PTEN is to maintain genome stability. Here, the authors show that PTEN depletion leads to mitotic spindle shortening and chromosome misalignment due to aberrant EG5 activation.
- Jinxue He
- , Zhong Zhang
- & Wen H. Shen
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Article
| Open AccessTwo functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation
The BubR1/Bub3 complex regulates chromosome segregation to enable proper kinetochore-microtubule interactions and is also required for the spindle assembly checkpoint. Here the authors show that two distinct pools of BubR1/Bub3 exist at kinetochores to support both known functions of BubR1/Bub3.
- Gang Zhang
- , Blanca Lopez Mendez
- & Jakob Nilsson
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Article
| Open AccessHomologous recombination-dependent repair of telomeric DSBs in proliferating human cells
Telomeres protect the ends of chromosomes from the DNA damage recognition machinery, however how damage in telomeres is repaired is poorly understood. Here the authors use CRISPR-Cas9 to induce DNA breaks and identify proliferation dependent homologous recombination repair.
- Pingsu Mao
- , Jingfan Liu
- & Yong Zhao
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Review Article
| Open AccessHow to make a sex chromosome
Sex chromosome evolution begins when recombination between a homologous pair of chromosomes is halted. Here, Wright et al.review our current understanding of the causes and mechanisms of recombination suppression between incipient sex chromosomes and suggest future directions for the field.
- Alison E. Wright
- , Rebecca Dean
- & Judith E. Mank
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Article
| Open AccessGeneration of mice with longer and better preserved telomeres in the absence of genetic manipulations
Telomere shortening has been linked to some aspects of organismal ageing. Here the authors create chimaeric mice that contain a mix of cells with normal or unnaturally long telomeres, and show chimaeric mice are protected from some forms of ageing-associated cellular damage and have accelerated wound-healing.
- Elisa Varela
- , Miguel A. Muñoz-Lorente
- & Maria A. Blasco
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Article
| Open AccessEssential role of the Cdk2 activator RingoA in meiotic telomere tethering to the nuclear envelope
CDKs play central roles in cell cycle regulation and are normally activated by cyclins. Here the authors show that RingoA induces a cyclin-independent function of CDK2 at meiotic telomeres, which regulates their tethering to the nuclear envelope and proper synapsis of homologous chromosomes.
- Petra Mikolcevic
- , Michitaka Isoda
- & Angel R. Nebreda
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Article
| Open AccessGenome scale patterns of supercoiling in a bacterial chromosome
Bacterial DNA primarily exists in a negatively supercoiled or under-wound state. Here, by mapping the supercoiling state, the authors show that there is a gradient of supercoiling across the bacterial chromosome with the terminus being more negatively supercoiled than the origin.
- Avantika Lal
- , Amlanjyoti Dhar
- & Sankar Adhya
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Article
| Open AccessTRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions
While yeast Rap1 regulates telomere length and protects telomeres from non-homologous end joining, its role in higher eukaryotes is controversial. Here the authors present evidence that in mammals, RAP1 cooperates with TRF2 to prevent homologous recombination-mediated repair of telomeres.
- Rekha Rai
- , Yong Chen
- & Sandy Chang
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Article
| Open AccessShugoshin forms a specialized chromatin domain at subtelomeres that regulates transcription and replication timing
A chromosome is composed of structurally and functionally distinct domains. Here, Tashiro et al. report that the conserved centromeric protein Sgo2 localizes at the subtelomeres preferentially during G2phase and is essential for the formation of a highly condensed subtelomeric chromatin body “knob”.
- Sanki Tashiro
- , Tetsuya Handa
- & Junko Kanoh
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Article
| Open AccessA role for Separase in telomere protection
Drosophila telomeres are elongated by transposition of specialized retroelements rather than telomerase activity. Here, the authors show that Separase is enriched at Drosophila telomeres and loss of Sse, the gene encoding Separase, leads to telomere defects, suggesting a role for Separase in telomere protection.
- Francesca Cipressa
- , Patrizia Morciano
- & Giovanni Cenci
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Article
| Open AccessCep57 is a Mis12-interacting kinetochore protein involved in kinetochore targeting of Mad1–Mad2
The spindle assembly checkpoint relies on the accumulation of Mad1-Mad2 at kinetochores, but the mechanism of regulation is not known. Here Zhou et al. show that the centrosomal protein Cep57 interacts with the kinetochore proteins Mis12 and Mad1, and regulates the recruitment of Mad1/Mad2 to kinetochores.
- Haining Zhou
- , Tianning Wang
- & Jianguo Chen
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Article
| Open AccessElevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions
TRF2 is a member of the shelterin complex, essential in protecting telomeres from end-to-end fusions; however, increased levels of TRF2 are associated with cancer. Here, the authors show overexpression of TRF2 results in genomic instability through replication fork stalling and chromosome fusions.
- Bernadette Nera
- , Hui-Shun Huang
- & Lifeng Xu
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Article
| Open AccessAn Xist-activating antisense RNA required for X-chromosome inactivation
The X-chromosome linked long non-coding RNA, Xist, is a master regulator of the X inactivation. Here, the authors report that XistAR, an Xist anti-sense long non-coding RNA encoded within the mouse Xist gene and transcribed only from the inactive X chromosome, regulates Xistexpression.
- Mrinal K. Sarkar
- , Srimonta Gayen
- & Sundeep Kalantry
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Article
| Open AccessThe DNA structure and sequence preferences of WRN underlie its function in telomeric recombination events
The loss of WRN helicase leads to abnormalities at chromosome ends and is associated with premature ageing phenotypes characteristic of Werner syndrome. Here the authors show that WRN acts in a structure- and sequence-specific manner on recombination intermediates relevant to telomere maintenance.
- Deanna N. Edwards
- , Amrita Machwe
- & David K. Orren
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Article
| Open AccessBub1 autophosphorylation feeds back to regulate kinetochore docking and promote localized substrate phosphorylation
Bub1 kinase phosphorylates histone H2A-T120 at the centromere to recruit shugoshin proteins and promote sister chromatid cohesion during mitosis. Here the authors show that Bub1 autophosphorylation on T589 influences Bub1 dynamics at the kinetochore and restricts H2A-T120 phosphorylation to centromeres.
- Adeel Asghar
- , Audrey Lajeunesse
- & Sabine Elowe
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Article
| Open AccessTelomere maintenance through recruitment of internal genomic regions
Telomeres in post-crisis cells are maintained by re-activated telomerase or by alternative lengthening of telomeres (ALT). Here, Seo et al. report a stable mode of ALT in worm where internal genomic regions generate a genomic reservoir ready to be incorporated into telomeres upon ALT activation.
- Beomseok Seo
- , Chuna Kim
- & Junho Lee
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Article
| Open AccessProteomics of yeast telomerase identified Cdc48-Npl4-Ufd1 and Ufd4 as regulators of Est1 and telomere length
Regulating telomere length and telomerase activity are critical biological processes implicated in ageing and cancer. Here the authors use mass spectrometry to identify the Cdc48-Npl4-Ufd1 complex, which targets proteins for degradation, as a novel regulator of the yeast telomerase Est1.
- Kah-Wai Lin
- , Karin R. McDonald
- & Virginia A. Zakian
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Article
| Open AccessTelomeres are partly shielded from ultraviolet-induced damage and proficient for nucleotide excision repair of photoproducts
DNA damage caused by ultraviolet irradiation is removed from the genome by nucleotide excision repair; however, it is unclear if this occurs at chromosome ends. Here the authors provide evidence indicating that telomeres are partially shielded from damage and that repair is fully functional.
- Dhvani Parikh
- , Elise Fouquerel
- & Patricia L. Opresko
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Article
| Open AccessA quantitative description of Ndc80 complex linkage to human kinetochores
The Ndc80 complex acts as an interface between kinetochores and spindle microtubules, and is recruited to the kinetochore by several different proteins. Suzukiet al. use protein counting techniques and RNA interference to quantify the interaction stoichiometries within this intricate cellular structure.
- Aussie Suzuki
- , Benjamin L. Badger
- & Edward D. Salmon