Featured
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Letter |
Transcript-RNA-templated DNA recombination and repair
Endogenous RNA transcripts are shown to mediate recombination with yeast chromosomal DNA; as the level of RNAs in the nucleus is quite high, these results may open up new understanding of the plasticity of repair and genome instability mechanisms.
- Havva Keskin
- , Ying Shen
- & Francesca Storici
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Letter |
Avoidance of ribonucleotide-induced mutations by RNase H2 and Srs2-Exo1 mechanisms
Srs2 helicase facilitates the removal of ribonucleoside monophosphates that are incorrectly incorporated into DNA during replication.
- Catherine J. Potenski
- , Hengyao Niu
- & Hannah L. Klein
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Letter |
BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2
BRCA2, the breast cancer susceptibility gene factor, interacts with TREX-2, a protein complex involved in the biogenesis and export of messenger ribonucleoprotein, to process DNA–RNA hybrid structures called R-loops that can trigger genome instability; these may be a central cause of the stress occurring in early cancer cells that drives oncogenesis.
- Vaibhav Bhatia
- , Sonia I. Barroso
- & Andrés Aguilera
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Article |
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
In order to find a general treatment for cancer, this study found that MTH1 activity is essential for the survival of transformed cells, and isolated two small-molecule inhibitors of MTH1, TH287 and TH588 — in the presence of these inhibitors, damaged nucleotides are incorporated into DNA only in cancer cells, causing cytotoxicity and eliciting a beneficial response in patient-derived mouse xenograft models.
- Helge Gad
- , Tobias Koolmeister
- & Thomas Helleday
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Letter |
Structural basis for translocation by AddAB helicase–nuclease and its arrest at χ sites
A dual-function helicase–nuclease, typified by RecBCD in Escherichia coli, acts on free DNA ends during bacterial double-stranded break repair until it reaches a χ sequence at which it pauses before continuing with modified enzymatic properties; here several crystal structures of the related AddAB enzyme from Bacillus subtilis bound to χ-containing DNA are presented, offering insight into χ recognition and its effect on DNA translocation.
- Wojciech W. Krajewski
- , Xin Fu
- & Dale B. Wigley
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Article |
UvrD facilitates DNA repair by pulling RNA polymerase backwards
UvrD acts in nucleotide excision repair by using its helicase/translocase activity to induce RNA polymerase backtracking, enabling repair enzymes to access DNA lesions.
- Vitaly Epshtein
- , Venu Kamarthapu
- & Evgeny Nudler
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Letter |
RecA bundles mediate homology pairing between distant sisters during DNA break repair
RecA bundles are shown to be important for the pairing of homologous loci that have segregated to opposite ends of the cell during DNA double-strand break repair in vivo in Escherichia coli.
- Christian Lesterlin
- , Graeme Ball
- & David J. Sherratt
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Letter |
Aprataxin resolves adenylated RNA–DNA junctions to maintain genome integrity
This study shows that aprataxin, encoded by a gene mutated in the neurodegenerative disorder AOA1, can remove the 5′ AMP from RNA–DNA junctions; this RNA–DNA damage response promotes cell survival.
- Percy Tumbale
- , Jessica S. Williams
- & R. Scott Williams
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Letter |
Migrating bubble during break-induced replication drives conservative DNA synthesis
This paper demonstrates that the mechanism of break-induced replication (BIR) is significantly different from S-phase replication, as it proceeds via a migrating bubble driven by Pif1 helicase, results in conservative inheritance of newly synthesized DNA, and is inherently mutagenic.
- Natalie Saini
- , Sreejith Ramakrishnan
- & Anna Malkova
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Letter |
HELQ promotes RAD51 paralogue-dependent repair to avert germ cell loss and tumorigenesis
Interstrand crosslink (ICL) repair involves proteins whose mutation results in the disorder Fanconi anaemia: here gene knockdown studies in mice show that the absence of HELQ, a protein previously implicated in ICL repair, compromises germ cell development and results in tumour predisposition due to defective recombination at damaged replication forks.
- Carrie A. Adelman
- , Rafal L. Lolo
- & Simon J. Boulton
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Letter |
DNA unwinding heterogeneity by RecBCD results from static molecules able to equilibrate
The bacterial RecBCD helicase/nuclease shows broad, and apparently static, heterogeneity in the unwinding rate manifest by individual molecules: here it is shown that transiently halting an enzyme during processive translocation allows for a change, most likely conformational, such that the velocity of the molecule after pausing can fall anywhere within the spectrum of rates seen for a population.
- Bian Liu
- , Ronald J. Baskin
- & Stephen C. Kowalczykowski
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Article |
53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark
This study shows that 53BP1 recruitment to sites of DNA damage involves dual recognition of H4K20me2 and H2AK15 histone ubiquitination; the ubiquitin mark and the surrounding epitope on H2A are read by a region of 53BP1 designated the ubiquitination-dependent recruitment motif.
- Amélie Fradet-Turcotte
- , Marella D. Canny
- & Daniel Durocher
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Letter |
The bromodomain protein Brd4 insulates chromatin from DNA damage signalling
Isoform B of the chromatin-binding protein Brd4 acts to suppress DNA damage response signalling.
- Scott R. Floyd
- , Michael E. Pacold
- & Michael B. Yaffe
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Article |
KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling
KAT5 tyrosine phosphorylation, mediated by the tyrosine kinase c-Abl, increases after DNA damage, promoting KAT5 binding to histone H3K9me3, which triggers KAT5-mediated acetylation of the ATM kinase; this promotes the activation of the DNA damage checkpoint and cell survival.
- Abderrahmane Kaidi
- & Stephen P. Jackson
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Letter |
MicroRNA-34a regulates cardiac ageing and function
A role is demonstrated for miR-34a, a microRNA that is upregulated in the ageing heart; miR-34a downregulates PNUTS, a protein that protects cardiomyocytes and telomeres, silencing of miR-34a is therefore a promising therapeutic target.
- Reinier A. Boon
- , Kazuma Iekushi
- & Stefanie Dimmeler
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Letter |
A two-step mechanism for TRF2-mediated chromosome-end protection
The telomere-biding protein TRF2 is shown to protect telomeres from activating the DNA-damage response through two mechanisms: preventing the activation ATM kinase through its dimerization domain, in addition to independently suppressing signalling events occurring downstream of ATM.
- Keiji Okamoto
- , Cristina Bartocci
- & Eros Lazzerini Denchi
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Letter |
Recombination-restarted replication makes inverted chromosome fusions at inverted repeats
A new mechanism of chromosomal rearrangement is identified through the observation that broken or collapsed DNA replication forks restarted by homologous recombination have a high propensity for U-turns at short inverted repeats; the error-prone nature of this mechanism is suggested to contribute to gross chromosomal rearrangements and copy-number variations present in cancer and other genomic disorders.
- Ken’Ichi Mizuno
- , Izumi Miyabe
- & Johanne M. Murray
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Letter |
Post-replicative repair involves separase-dependent removal of the kleisin subunit of cohesin
Cohesin, which tethers sister chromatids together, is found to be cleaved by separase after DNA damage, resulting in cohesin dissociation and allowing for post-replicative repair of DNA double-strand breaks.
- Alexandra McAleenan
- , Andres Clemente-Blanco
- & Luis Aragón
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Letter |
Coordinated control of replication and transcription by a SAPK protects genomic integrity
Upregulation of gene transcription in stressed cells can lead to clashes between the transcription and repair machineries; here, a stress-activated protein kinase (SAPK), Hog1, is shown to coordinate these two processes in yeast.
- Alba Duch
- , Irene Felipe-Abrio
- & Francesc Posas
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Letter |
DNA-repair scaffolds dampen checkpoint signalling by counteracting the adaptor Rad9
DNA damage or replication stress induces the activation of checkpoint kinases, pausing the cell cycle so that DNA repair can take place; checkpoint activation must be regulated to prevent the cell-cycle arrest from persisting after damage is repaired, and now the Slx4–Rtt107 complex is shown to regulate checkpoint kinase activity by directly monitoring DNA-damage signalling.
- Patrice Y. Ohouo
- , Francisco M. Bastos de Oliveira
- & Marcus B. Smolka
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News & Views |
A glimpse of molecular competition
Single-molecule studies reveal how the DNA-repair protein RecA overcomes competition from another protein to bind to single-stranded DNA, and how other mediator proteins assist in this process. See Letter p.274
- Susan T. Lovett
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Letter |
Direct imaging of RecA nucleation and growth on single molecules of SSB-coated ssDNA
Single-molecule analysis of RecA filament assembly on its in vivo substrate, SSB-coated single-stranded DNA, reveals that a dimer of RecA is required for nucleation, and is followed by bidirectional growth of the filament through monomer addition; the recombination mediator RecOR accelerates nucleation and growth, and the addition of RecF further stimulates nucleation.
- Jason C. Bell
- , Jody L. Plank
- & Stephen C. Kowalczykowski
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Letter |
Initiation of transcription-coupled repair characterized at single-molecule resolution
The early stages of transcription-coupled DNA repair are observed at single-molecule resolution; the Escherichia coli DNA translocase molecule Mfd is shown to promote RNA polymerase dissociation by catalysing two irreversible, ATP-dependent transitions.
- Kévin Howan
- , Abigail J. Smith
- & Terence R. Strick
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Letter |
The Fun30 nucleosome remodeller promotes resection of DNA double-strand break ends
Nucleolytic degradation of 5′ strands at DNA double-strand breaks in yeast is shown to be facilitated by the nucleosome remodeller Fun30, particularly within chromatin bound by the checkpoint adaptor protein known to inhibit resection, Rad9.
- Xuefeng Chen
- , Dandan Cui
- & Grzegorz Ira
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Letter |
Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function
The function of haematopoietic stem and progenitor cells is impaired by damaged DNA; here, endogenously generated aldehydes are found to be one source of such damage, which is repaired by the Fanconi anaemia pathway.
- Juan I. Garaycoechea
- , Gerry P. Crossan
- & Ketan J. Patel
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Letter |
Single-molecule imaging of DNA pairing by RecA reveals a three-dimensional homology search
The search for DNA homology is vital to recombinational DNA repair and occurs by intersegment contact sampling wherein the three-dimensional conformational state of the double-stranded DNA target and the length of the homologous RecA–single-stranded DNA filament have important roles.
- Anthony L. Forget
- & Stephen C. Kowalczykowski
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Article |
DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes
A genome-wide analysis determines the contribution of DNA breaks and nuclear interactions to the formation of random versus recurrent translocations; whereas random translocations follow nuclear interaction profiles, the frequency of recurrent translocations is directly proportional to the amount of DNA damage at translocation partners.
- Ofir Hakim
- , Wolfgang Resch
- & Rafael Casellas
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Article |
DNA breaks and chromosome pulverization from errors in mitosis
Chromosomes within micronuclei are shown to be damaged during S phase and become highly fragmented, and the damaged pieces can be reincorporated into the genome.
- Karen Crasta
- , Neil J. Ganem
- & David Pellman
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Letter |
Rad51 paralogues Rad55–Rad57 balance the antirecombinase Srs2 in Rad51 filament formation
- Jie Liu
- , Ludovic Renault
- & Wolf-Dietrich Heyer
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Letter |
Bidirectional resection of DNA double-strand breaks by Mre11 and Exo1
- Valerie Garcia
- , Sarah E. L. Phelps
- & Matthew J. Neale
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Letter |
RNAi promotes heterochromatic silencing through replication-coupled release of RNA Pol II
- Mikel Zaratiegui
- , Stephane E. Castel
- & Robert A. Martienssen
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Research Highlights |
Stomach bacteria break DNA strands
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Research Highlights |
Cell death from failure of DNA fix
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Letter |
A stress response pathway regulates DNA damage through β2-adrenoreceptors and β-arrestin-1
- Makoto R. Hara
- , Jeffrey J. Kovacs
- & Robert J. Lefkowitz
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Letter |
Protection of repetitive DNA borders from self-induced meiotic instability
- Gerben Vader
- , Hannah G. Blitzblau
- & Andreas Hochwagen
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News & Views |
Alcohol, DNA and disease
Acetaldehyde, a reactive metabolite of ethanol, can damage DNA unless properly processed. A biochemical pathway involved in Fanconi anaemia seems to be essential for protection against such damage. See Article p.53
- Hans Joenje
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Article |
Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice
- Frédéric Langevin
- , Gerry P. Crossan
- & Ketan J. Patel
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News & Views |
Cyclin D1 multitasks
Cyclin D1 is one of the drivers of the cell cycle, and its deregulation may promote the development of tumours. Surprisingly, this protein also mediates the repair of damaged DNA, a mechanism that commonly prevents cancer. See Letter p.230
- Jiri Bartek
- & Jiri Lukas
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Letter |
A function for cyclin D1 in DNA repair uncovered by protein interactome analyses in human cancers
- Siwanon Jirawatnotai
- , Yiduo Hu
- & Piotr Sicinski
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Research Highlights |
Cells stressed from hunger
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Research Highlights |
Radiation's double whammy
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Letter |
Crucial role for DNA ligase III in mitochondria but not in Xrcc1-dependent repair
Eukaryotic cells have several DNA ligases. DNA ligase III (Lig3) forms a complex with Xrcc1 that can function in nuclear repair. But, Lig3 null animals cannot be made; is this nuclear role in base excision repair its critical function? This is one of two papers showing that the role of Lig3 in the nucleus is non-essential. Rather, the catalytic activity of Lig3, but not Xrcc1, is essential for the maintenance of mitochondria.
- Deniz Simsek
- , Amy Furda
- & Maria Jasin
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Letter |
DNA ligase III is critical for mtDNA integrity but not Xrcc1-mediated nuclear DNA repair
In the nucleus, a complex of DNA ligase III (Lig3) and Xrcc1 catalyses the last step of base excision repair. Inactivation of Lig3 in the mouse leads to early embryonic lethality, but the critical role played by Lig3 in viability is unknown. This study shows, using conditional knockouts of Lig3 in the nervous system and cardiac muscle, that its essential function is maintenance of mitochondrial DNA integrity. The results also indicate distinct functional roles for Lig3 and Xrcc1.
- Yankun Gao
- , Sachin Katyal
- & Peter J. McKinnon
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News & Views |
The expanding arena of DNA repair
The protein Sae2 mediates the repair of double-strand breaks in DNA. It emerges that Sae2 activity is controlled by both its modification with acetyl groups and its degradation by the process of autophagy. See Article p.74
- Catherine J. Potenski
- & Hannah L. Klein
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Article |
HDACs link the DNA damage response, processing of double-strand breaks and autophagy
The presence of DNA lesions is a clear signal that initiates the DNA damage response; however, the mechanisms that attenuate this response when repair has occurred are less clear. Here, deacetylation of Sae2 by Rpd3 and Hda1 is shown to be required for it to act on Mre11. When the role of Sae2 in resection is completed, it is acetylated by Gcn5 and degraded through an autophagic pathway. This work highlights links between DNA damage signalling, acetylation of repair factors, and autophagy mediated degradation of these factors.
- Thomas Robert
- , Fabio Vanoli
- & Marco Foiani
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Research Highlights |
When DNA repair goes wrong
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Letter |
MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites
Recruitment of 53BP1 to double-strand DNA breaks is an important step in the cellular response to DNA damage. Here, the histone methyltransferase MMSET is shown to be responsible for localized increases in a histone modification that is involved in recruiting 53BP1. The mechanism of MMSET recruitment to DNA damage sites is also investigated.
- Huadong Pei
- , Lindsey Zhang
- & Zhenkun Lou