Featured
-
-
Article |
TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer
Squamous cell carcinoma of the head and neck often becomes resistant to treatment. In this study, Banerjee et al. show that the ATPase TRIP13 can mediate resistance in cells from these tumours by inducing error prone non-homologous end joining DNA repair.
- Rajat Banerjee
- , Nickole Russo
- & Nisha J. D’Silva
-
Article |
The fidelity of the ligation step determines how ends are resolved during nonhomologous end joining
DNA double strand breaks result in various types of damaged termini and are resolved by non-homologous end joining, but how cells coordinate the different steps that occur during repair is not clear. Here the authors show that a DNA ligase coordinates processing prior to the ligation step to limit errors.
- Crystal A. Waters
- , Natasha T. Strande
- & Dale A. Ramsden
-
Article |
A histone H3K36 chromatin switch coordinates DNA double-strand break repair pathway choice
DNA double strand breaks are repaired by nonhomologous end-joining (NHEJ) or homologous recombination (HR) pathways. Here, Pai et al.discover that post-translational modification of lysine 36 of histone H3 plays a key role in determining double strand repair pathway choice.
- Chen-Chun Pai
- , Rachel S. Deegan
- & Timothy C. Humphrey
-
Article |
An RNA polymerase II-coupled function for histone H3K36 methylation in checkpoint activation and DSB repair
Chromatin modifications play a fundamental role in regulating the cellular response to DNA damage. Here, Jha and Strahl identify methylation of histone H3 on lysine 36 mediated by the histone-methyltransferase Set2 as a regulator of chromatin remodelling at double-strand breaks that affects DNA repair.
- Deepak Kumar Jha
- & Brian D. Strahl
-
Article
| Open AccessHomeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing
Cells exposed to DNA damage delay mitotic entry to allow repair. Liang et al. unexpectedly find that the duration of arrest and the completeness of repair vary from cell to cell, determined by progressively increasing polo-like kinase-1 activity, which must pass a threshold to trigger mitosis.
- Hongqing Liang
- , Alessandro Esposito
- & Ashok R. Venkitaraman
-
Article |
Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity
Nucleotide excision repair protects the genome from UV light-induced damage. Here, Puumalainen et al. show that chromatin retention of the UV lesion sensors DDB2 and XPC due to a lack of p97 segregase impairs excision repair, revealing that DNA lesion-associated protein homeostasis affects genome stability.
- Marjo-Riitta Puumalainen
- , Davor Lessel
- & Hanspeter Naegeli
-
Article |
Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice
Cell cycle regulation of the two major DNA double-strand break repair pathways—NHEJ and HR—is critical for the maintenance of genome integrity. Here, Tomimatsu et al. show that phosphorylation of the nuclease EXO1 by cyclin-dependent kinases affects repair pathway choice by controlling long-range resection.
- Nozomi Tomimatsu
- , Bipasha Mukherjee
- & Sandeep Burma
-
Article
| Open AccessATM specifically mediates repair of double-strand breaks with blocked DNA ends
The role of ATM in DNA double-strand break (DSB) signalling is well established, but its function in the repair process remains controversial. Here, Álvarez-Quilón et al.show that ATM acts in the joining of blocked DSBs, uncovering DNA end structure as a key factor determining ATM involvement in DSB repair.
- Alejandro Álvarez-Quilón
- , Almudena Serrano-Benítez
- & Felipe Cortés-Ledesma
-
Article |
Genome-wide transcriptome profiling of homologous recombination DNA repair
Defects in the homologous recombination repair of DNA can result in gene mutation and cancer. In this study, Peng et al.identify a gene signature associated with homologous recombination repair deficiency and show that this can be used both to predict repair defects and clinical outcome in cancer patients.
- Guang Peng
- , Curtis Chun-Jen Lin
- & Shiaw-Yih Lin
-
Article
| Open AccessThe nucleosome acidic patch plays a critical role in RNF168-dependent ubiquitination of histone H2A
The E3 ubiquitin ligase RNF168 ubiquitinates specific lysines on histone H2A as part of the DNA damage response. Here, the authors show that the acidic patch on the histone H2A/H2B dimer catalyses RNF168-dependent ubiquitination of histone 2A by redirecting ubiquitination activity towards the relevant target lysines.
- Francesca Mattiroli
- , Michael Uckelmann
- & Titia K. Sixma
-
Article |
A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites
Genomes contain tracts of tandem guanines, which can adopt stable G-quadruplex structures that obstruct replication fork movement. Here, Koole et al. describe a non-canonical polymerase Theta-dependent repair pathway that prevents genomic instability caused by these replication barriers.
- Wouter Koole
- , Robin van Schendel
- & Marcel Tijsterman
-
Article |
Efficient genome engineering by targeted homologous recombination in mouse embryos using transcription activator-like effector nucleases
Genetically engineered mice are an important aspect of human disease research. Here, the authors use artificial transcription activator-like effector-nucleases to generate a mouse line with a conditionally targeted allele and suggest that this method can be easily adapted to any gene in the mouse genome.
- Daniel Sommer
- , Annika E. Peters
- & Marc Beyer
-
Article |
TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster
Human TCTP, a highly conserved protein linked to tumorigenesis, has been implicated in the cellular DNA damage response in an ATM kinase-dependent manner. Here, Hong et al. demonstrate in vivo that DrosophiladTCTP controls genome stability by enhancing dATM activity towards its substrate H2Av.
- Sung-Tae Hong
- & Kwang-Wook Choi
-
Article |
ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets
The tumour suppressor ARF regulates p53 levels; however, in contrast to p53, ARF has not been implicated in the response to DNA damage. In this study, Carlos et al.show that single-stranded DNA formed in BRCA2-null cells triggers a DNA damage response leading to the activation of ARF and senescence.
- Ana Rita Carlos
- , Jose Miguel Escandell
- & Madalena Tarsounas
-
Article
| Open AccessBase excision repair AP endonucleases and mismatch repair act together to induce checkpoint-mediated autophagy
The chemotherapeutic drug 5-fluorouracil causes cell toxicity by inducing DNA lesions. Here, SenGupta et al. use C. elegansto show that components of the base excision repair and the mismatch repair pathways function together in the response to 5-fluorouracil, resulting in activation of the DNA damage checkpoint and induction of autophagy.
- Tanima SenGupta
- , Maria Lyngaas Torgersen
- & Hilde Nilsen
-
Article |
Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing
Reduced rates of cell proliferation are thought to contribute to age-related tissue dysfunction. Here Pruitt et al.induce expression of the cell cycle inhibitor Cdkn1b in adult mice and show that this recapitulates ageing-related defects in tissue maintenance.
- Steven C. Pruitt
- , Amy Freeland
- & Gillian K. Cady
-
Article
| Open AccessRecG and UvsW catalyse robust DNA rewinding critical for stalled DNA replication fork rescue
The helicases UvsW and RecG have both unwinding and rewinding activities and are involved in the rescue of stalled DNA replication forks. Here Manosas et al. use single-molecule techniques to characterize the rewinding activities of the two helicases, concluding that rewinding is actively catalysed.
- Maria Manosas
- , Senthil K. Perumal
- & Vincent Croquette
-
Article
| Open AccessATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy
The protein ATG5 is known to be involved in the formation of autophagosomes. Here, Maskey et al. identify a new role of ATG5 in response to drug-induced DNA damage whereby ATG5 translocates to the nucleus, leading to chromosome misalignment and mitotic catastrophe.
- Dipak Maskey
- , Shida Yousefi
- & Hans-Uwe Simon
-
Article
| Open AccessR-loops and nicks initiate DNA breakage and genome instability in non-growing Escherichia coli
DNA double-strand breaks commonly occur in all replicating cells. Wimberly and colleagues show that in non-replicating cells, aborted transcription/translation forms RNA/DNA hybrid R-loops that prime origin-independent replication, leading to DNA breakage, point mutations and chromosomal rearrangements.
- Hallie Wimberly
- , Chandan Shee
- & P. J. Hastings
-
Article |
DNA repair choice defines a common pathway for recruitment of chromatin regulators
Chromatin regulators facilitate repair of DNA double-strand breaks in chromosomal DNA. The authors show that the recruitment of such chromatin regulators to DNA lesions is controlled by the choice of DNA repair pathway.
- Gwendolyn Bennett
- , Manolis Papamichos-Chronakis
- & Craig L. Peterson
-
Article |
Regulation of the DNA damage response on male meiotic sex chromosomes
The XY body is a structure required for silencing of sex chromosomes, which is enriched in DNA damage response proteins during meiosis in male germ cells. Here, the authors identify differences between the regulation of the DNA damage response at the XY body and in somatic cells.
- Lin-Yu Lu
- , Yi Xiong
- & Xiaochun Yu
-
Article |
A functional deficiency of TERA/VCP/p97 contributes to impaired DNA repair in multiple polyglutamine diseases
Mutations in polyglutamine proteins are implicated in neurodegenerative disorders. Okazawa and colleagues now demonstrate that mutant polyQ proteins interact directly with the ATPase TERA, resulting in reduced DNA double-strand break repair, which is a feature of neurodegenerative diseases.
- Kyota Fujita
- , Yoko Nakamura
- & Hitoshi Okazawa
-
Article |
A new protein complex promoting the assembly of Rad51 filaments
RecA/Rad51 proteins catalyse the recognition and exchange between two homologous DNA strands during homologous recombination. Sasanuma et al. now demonstrate that Rad51 association with ssDNA is mediated by a complex consisting of Psy3, Csm2, Shu1 and Shu2 proteins.
- Hiroyuki Sasanuma
- , Maki S. Tawaramoto
- & Akira Shinohara
-
Article |
Two sequential cleavage reactions on cruciform DNA structures cause palindrome-mediated chromosomal translocations
Palindromic DNA sequences in the genome can cause gross chromosomal rearrangements. Inagaki et al.demonstrate how the pathways of Holliday-junction resolution and antigen-receptor gene rearrangement interact to process cruciform conformation of palindrome DNA into chromosomal translocations in human embryonic kidney cells.
- Hidehito Inagaki
- , Tamae Ohye
- & Hiroki Kurahashi
-
Article |
FBH1 co-operates with MUS81 in inducing DNA double-strand breaks and cell death following replication stress
DNA replication stress promotes genome instability and cell death. Here Fugger et al.describe how FBH1, via its helicase activity, is required to eliminate cells with excessive DNA replication stress, through the generation of MUS81-induced DNA double-strand breaks.
- Kasper Fugger
- , Wai Kit Chu
- & Claus Storgaard Sørensen
-
Article |
FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chunget al. show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.
- Young Min Chung
- , See-Hyoung Park
- & Mickey C.-T. Hu
-
Article |
A crucial role for bone morphogenetic protein-Smad1 signalling in the DNA damage response
The bone morphogenetic protein (BMP) and Smad1 signalling pathway is required for embryogenesis. In this study, Smad1 is shown to be phosphorylated by Atm in response to DNA damage and this results in elevated Smad1 signalling, thus uncovering a new role for this pathway in the DNA damage response.
- Jenny Fung Ling Chau
- , Deyong Jia
- & Baojie Li
-
Article |
Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
-
Article
| Open AccessSUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair
Tyrosyl DNA phosphodiesterase 1 (TDP1) repairs DNA breaks and is mutated in the disease Spinocerebellar Ataxia with Axonal Neuropathy. Here TDP1 is shown to be post-translationally modified by sumoylation of lysine 111, and cells carrying a mutation at this residue are inefficient at single-strand DNA break repair.
- Jessica J.R. Hudson
- , Shih-Chieh Chiang
- & Sherif F. El-Khamisy
-
Article
| Open AccessTelomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence
Irreparable DNA damage leads to apoptosis or senescence. Hewittet al. show that, in response to genotoxic or oxidative stress, DNA damage occurs predominantly at telomere associated foci, which accumulate with age in vivo, irrespective of telomerase activity.
- Graeme Hewitt
- , Diana Jurk
- & João F. Passos
-
Article |
Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
PADI4 is an enzyme that converts arginine residues to citrulline. Here, Tanikawa and colleagues show that, in response to DNA damage, histone H4 and Lamin C are citrullinated in a p53 and PADI4-dependent manner andPadi4-dependent manner and Padi4 null mice are resistant to radiation-induced apoptosis in the thymus.
- Chizu Tanikawa
- , Martha Espinosa
- & Koichi Matsuda
-
Article
| Open AccessBRCA1 is an essential regulator of heart function and survival following myocardial infarction
The tumour suppressor BRCA1 is mutated in familial breast and ovarian cancer. Now, Shuklaet al.demonstrate that mice lacking BRCA1 in cardiomyocytes are more sensitive to ischaemia than control mice, and that BRCA1 is elevated in human tissues exposed to ischaemia, suggesting a cardioprotective role for BRCA1.
- Praphulla C. Shukla
- , Krishna K. Singh
- & Subodh Verma
-
Article |
p53 and p16INK4A independent induction of senescence by chromatin-dependent alteration of S-phase progression
Cellular senescence is characterized by the cessation of cell growth and the expression of the p16 protein. In this study, inhibition or loss of p300, a histone acetyltransferase, is shown to result in senescence that occurs independently of p16 and is associated with histone hypoacetylation and altered replication timing.
- Alexandre Prieur
- , Emilie Besnard
- & Jean-Marc Lemaitre
-
Article
| Open AccessThe IncP-1 plasmid backbone adapts to different host bacterial species and evolves through homologous recombination
Plasmids are present in many bacteria and are often transferred between different species causing horizontal gene transfer. By comparing the sequences of 25 plasmid DNA backbones, the authors show that homologous recombination is prevalent in plasmids and that the plasmids have adapted to persist in different host bacteria.
- Peter Norberg
- , Maria Bergström
- & Malte Hermansson
-
Article |
ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA
Uridines at the wobble position of transfer RNA anticodons are usually modified to allow efficient decoding of messenger RNA codons. In this study, ALKBH8 is shown to be a bifunctional transfer RNA modification enzyme required for the formation of a novel diastereomeric pair of modified wobble uridines.
- Erwin van den Born
- , Cathrine B. Vågbø
- & Pål Ø. Falnes
-
Article |
Mitochondrial respiration protects against oxygen-associated DNA damage
Oxygen is necessary for mitochondrial respiration; however it can also result in the formation of toxic reactive species that can cause DNA damage. Using cells defective in respiration these authors demonstrate that mitochondria protect a cell from these harmful effects of oxygen.
- Ho Joong Sung
- , Wenzhe Ma
- & Paul M. Hwang