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Article
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Splice modulators target PMS1 to reduce somatic expansion of the Huntington’s disease-associated CAG repeat
Somatic expansion of a CAG repeat in HTT drives onset of Huntington’s disease. Using a human cell line model and splice modulators, here the authors show that PMS1 is an enhancer of CAG repeat expansion, making it a target for therapeutic intervention.
- Zachariah L. McLean
- , Dadi Gao
- & James F. Gusella
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| Open Access
Seeding the meiotic DNA break machinery and initiating recombination on chromosome axes
Meiotic cells deliberately break their DNA to allow chromosomes to swap genetic material. Here, authors reveal genetically separable pathways controlling the seeding and growth of chromosome-bound protein condensates responsible for DNA breaks.
- Ihsan Dereli
- , Vladyslav Telychko
- & Attila Tóth
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Dynamics of extrachromosomal circular DNA in rice
Comparing to other biological systems, our understanding of plant extrachromosomal circular DNA (eccDNA) is limited. Here, the authors profile eccDNA from six rice tissues and investigate eccDNA characteristics, formation mechanisms, distribution, and functional implications.
- Jundong Zhuang
- , Yaoxin Zhang
- & Tingting Lu
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Primase promotes the competition between transcription and replication on the same template strand resulting in DNA damage
Resolving R-loops caused by transcription-replication conflicts (TRCs) is vital to genome stability in organisms. Here, the authors show that the chloroplast-localized primase ATH intensifies template strand competition and exacerbates the Head-On TRCs induced DNA damage.
- Weifeng Zhang
- , Zhuo Yang
- & Qianwen Sun
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iMUT-seq: high-resolution DSB-induced mutation profiling reveals prevalent homologous-recombination dependent mutagenesis
DNA double-strand breaks (DSBs) are highly mutagenic making them central to many pathologies. Here, the authors developed a highly sensitive sequencing approach to study DSB mutagenesis, yielding insights into mutagenic outcomes and characterising their underlying mechanisms.
- Aldo S. Bader
- & Martin Bushell
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Gene duplication and deletion caused by over-replication at a fork barrier
Gene duplications and deletions are important drivers of evolution and disease. Here, the authors show that excess DNA generated at a replication fork barrier can be integrated at a new genomic site causing both a gene duplication and a deletion.
- Judith Oehler
- , Carl A. Morrow
- & Matthew C. Whitby
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TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription
Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs single strand breaks (SSBs) generated by DNA topoisomerase I (TOP1). Here the authors show that TDP1 also repairs TOP1-induced double strand breaks (DSBs).
- Diana Rubio-Contreras
- & Fernando Gómez-Herreros
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Double-strand breaks induce inverted duplication chromosome rearrangements by a DNA polymerase δ-dependent mechanism
Inverted duplications are a type of chromosome rearrangement observed in cancers. Here the authors show that a DNA double-strand break induces high frequency inverted duplications in cells lacking Mre11 nuclease by DNA polymerase δ-dependent mechanism.
- Amr M. Al-Zain
- , Mattie R. Nester
- & Lorraine S. Symington
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| Open Access
The chromatin network helps prevent cancer-associated mutagenesis at transcription-replication conflicts
Epigenetic alterations are frequent in human malignancies and have been shown to threaten genome integrity. Here the authors show that a chromatin network prevents R-loops and transcription-replication conflicts from genomic instability and mutagenic signatures frequently associated with cancer.
- Aleix Bayona-Feliu
- , Emilia Herrera-Moyano
- & Andrés Aguilera
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Genomic signatures of past and present chromosomal instability in Barrett’s esophagus and early esophageal adenocarcinoma
Genome complexity is a distinguishing feature of advanced cancers in contrast to precancerous conditions. Here, by analysing chromosomal copy-number evolution in early cancers and precancerous lesions of the oesophagus, the authors reveal signatures of ongoing chromosomal instability and its role in promoting tumour progression.
- Chunyang Bao
- , Richard W. Tourdot
- & Cheng-Zhong Zhang
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Reactivation of a somatic errantivirus and germline invasion in Drosophila ovaries
Yoth et al. report that some mobile retrovirus-like genetic elements, errantiviruses, pose a threat to genome integrity when reactivated in somatic gonadal tissue, showing that they can infect the oocyte and transpose into the germline genome.
- Marianne Yoth
- , Stéphanie Maupetit-Méhouas
- & Emilie Brasset
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A R-loop sensing pathway mediates the relocation of transcribed genes to nuclear pore complexes
Here the authors report that DNA:RNA hybrid-containing R-loop structures are sensed by the ssDNA-binding protein RPA, triggering their relocation to nuclear pore complexes and attenuating transcription-associated genetic instability.
- Arianna Penzo
- , Marion Dubarry
- & Benoit Palancade
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Rapid gene content turnover on the germline-restricted chromosome in songbirds
Songbirds have an extra chromosome with unknown function found only in their germline. This study assembles and compares this chromosome in two closely related nightingale species, finding large differences in genetic content and only one conserved gene with probable essential function.
- Stephen A. Schlebusch
- , Jakub Rídl
- & Radka Reifová
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Nuclear myosin VI maintains replication fork stability
Whether actin and associated molecules have roles in the nucleus is an active area of study. Here Shi et al. report a nuclear function of the actin-based motor myosin VI in protecting stalled replication forks from nuclease-mediated degradation.
- Jie Shi
- , Kristine Hauschulte
- & Hans-Peter Wollscheid
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ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion
The ATR kinase has essential functions apart from its role in DNA replication stress. Here the authors find that in mouse primary B cells ATR tempers the pace of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors.
- Demis Menolfi
- , Brian J. Lee
- & Shan Zha
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Detecting recurrent passenger mutations in melanoma by targeted UV damage sequencing
Genome sequencing has identified many recurrent mutations in melanoma. Here, we use targeted UV damage sequencing to show that many of these mutations are associated with UV damage hotspots that are linked to DNA binding by ETS transcription factors.
- Kathiresan Selvam
- , Smitha Sivapragasam
- & John J. Wyrick
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Contributions of replicative and translesion DNA polymerases to mutagenic bypass of canonical and atypical UV photoproducts
Vandenberg et al. identify differing roles of yeast DNA polymerases during accurate and mutagenic synthesis past common and rare ultraviolet light photoproducts. Similar mechanisms may contribute to driver mutations causing skin cancer in humans.
- Brittany N. Vandenberg
- , Marian F. Laughery
- & Steven A. Roberts
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Structure-forming CAG/CTG repeats interfere with gap repair to cause repeat expansions and chromosome breaks
Exposure of a structure-forming sequence within a single-stranded gap creates a fragile site, resulting in large deletions. Gap filling drives disease-causing CAG repeat expansions, with direction of instability determined by the identity of the sequence on the template strand of the gap.
- Erica J. Polleys
- , Isabella Del Priore
- & Catherine H. Freudenreich
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RETRACTED ARTICLE: Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer
Polymerase (POL) θ inhibitors display synthetic lethality in tumours with homologous recombination repair deficiency. Here, the authors demonstrate that POLθ inhibition with novobiocin activates the cGAS/STING pathway in BRCA-deficient cancers.
- Jeffrey Patterson-Fortin
- , Heta Jadhav
- & Geoffrey I. Shapiro
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The interferon stimulated gene-encoded protein HELZ2 inhibits human LINE-1 retrotransposition and LINE-1 RNA-mediated type I interferon induction
Proteomic analyses revealed that a group of interferon-stimulated genes suppresses LINE-1 retrotransposon activities, including HELZ2, which reduces LINE-1 RNA and the associated innate immune response levels.
- Ahmad Luqman-Fatah
- , Yuzo Watanabe
- & Tomoichiro Miyoshi
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Rad52’s DNA annealing activity drives template switching associated with restarted DNA replication
The restart of collapsed replication forks is associated with high rates of genomic rearrangement. Here, the authors show that during restart initiation rearrangements are driven mainly by Rad51, whereas during elongation they rely more on Rad52.
- Anastasiya Kishkevich
- , Sanjeeta Tamang
- & Matthew C. Whitby
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Transposable element-mediated rearrangements are prevalent in human genomes
Here the authors show that transposable element-mediated rearrangements impact more than 500 kbp of an average human genome, are a source of individual variation, a substrate for evolutionary change, and can occur through diverse mechanisms.
- Parithi Balachandran
- , Isha A. Walawalkar
- & Christine R. Beck
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Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy
The SMC5/6 complex is critical for genome stability. Here, the authors identify mutations in SLF2 and SMC5 as cause of Atelís Syndrome characterized by microcephaly, short stature, anemia, segmented chromosomes and mosaic variegated hyperploidy.
- Laura J. Grange
- , John J. Reynolds
- & Grant S. Stewart
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Epigenetic control of chromosome-associated lncRNA genes essential for replication and stability
Heskett et al. describe several members of a class of long non-coding RNAs, known as ASARs, which show distinct epigenetic regulation between subclonal lineages and are essential for normal DNA replication timing and stability of human autosomes.
- Michael B. Heskett
- , Athanasios E. Vouzas
- & Mathew J. Thayer
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The KU-PARP14 axis differentially regulates DNA resection at stalled replication forks by MRE11 and EXO1
Protection of replication forks against nucleolytic degradation is crucial for genome stability. Here, Dhoonmoon et al identify PARP14 and the KU complex as essential regulators of fork degradation by MRE11 and EXO1 nucleases in BRCA-deficient cells.
- Ashna Dhoonmoon
- , Claudia M. Nicolae
- & George-Lucian Moldovan
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The mechanism of replication stalling and recovery within repetitive DNA
DNA replication of repetitive sequences was recreated in a test tube using purified components. DNA alone was sufficient to induce stalling. Both stalling and recovery were dictated by the capacity of DNA to fold into unusual secondary structures.
- Corella S. Casas-Delucchi
- , Manuel Daza-Martin
- & Gideon Coster
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Precision digital mapping of endogenous and induced genomic DNA breaks by INDUCE-seq
Understanding how DNA double strand breaks (DSBs) form and are repaired in the genome depends on their accurate measurement. Here the authors describe INDUCE-seq; a DSB-detection method that simultaneously measures physiological and induced breaks throughout the genome.
- Felix M. Dobbs
- , Patrick van Eijk
- & Simon H. Reed
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Genome-wide mapping of individual replication fork velocities using nanopore sequencing
Theulot et al. introduce NanoForkSpeed, a nanopore sequencing-based method to map individual replication fork velocities on entire genomes. NFS shows that fork speed is uniform across yeast chromosomes except for a marked slowdown at pausing sites.
- Bertrand Theulot
- , Laurent Lacroix
- & Benoît Le Tallec
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Somatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression
Barrett’s esophagus is a pre-malignant condition that can progress to esophageal cancer. Here, the authors carry out whole genome sequencing of samples from patients who did or did not progress to cancer and find that mutations in many genes occur regardless of progression status, but also find features associated with progressive disease.
- Thomas G. Paulson
- , Patricia C. Galipeau
- & Xiaohong Li
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Weight-bearing activity impairs nuclear membrane and genome integrity via YAP activation in plantar melanoma
Acral melanoma affects the soles of the feet but the etiology is unknown. Here, the authors show that melanoma cells implanted into the foot pad of mice and exposed to mechanical stress show features of nuclear rupture, DNA damage, and Yap activation.
- Jimyung Seo
- , HyunSeok Kim
- & Joon Kim
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BRCA2-DSS1 interaction is dispensable for RAD51 recruitment at replication-induced and meiotic DNA double strand breaks
Mishra et al. have generated mice with a single amino acid substitution in BRCA2, which disrupts its interaction with DSS1 resulting in a severe HR defect. They show the interaction to be dispensable for HR at replication induced and meiotic DSBs.
- Arun Prakash Mishra
- , Suzanne A. Hartford
- & Shyam K. Sharan
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Multi-omic cross-sectional cohort study of pre-malignant Barrett’s esophagus reveals early structural variation and retrotransposon activity
The alterations associated with progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma are not fully characterised. Here, the authors perform a multi-omics analysis of a longitudinally-sampled BE patient cohort, identifying the impact of structural variants, including mobile elements, and the timing of molecular events during progression.
- A. C. Katz-Summercorn
- , S. Jammula
- & R. C. Fitzgerald
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| Open Access
Somatic PMK-1/p38 signaling links environmental stress to germ cell apoptosis and heritable euploidy
Here the authors show that elimination of germ cells carrying damaged genomes is regulated by intestinal stress signalling in nematodes. Failure of the intestinal signalling results in stress-induced aneuploidy indicating that environmental stress impacts inheritance.
- Najmeh Soltanmohammadi
- , Siyao Wang
- & Björn Schumacher
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Mechanism for inverted-repeat recombination induced by a replication fork barrier
Replication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. Here the authors use a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome to support a model for recombination of closely linked repeats at stalled replication forks.
- Léa Marie
- & Lorraine S. Symington
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Helicase Q promotes homology-driven DNA double-strand break repair and prevents tandem duplications
Microhomology-mediated end-joining (MMEJ) is a poorly defined mutagenic DNA break repair pathway. Here the authors show that the helicase HELQ is essential for polymerase theta-independent MMEJ, single-strand annealing and homologous recombination through synthesis dependent strand annealing in C. elegans.
- J. A. Kamp
- , B. B. L. G. Lemmens
- & M. Tijsterman
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Counteraction between Astrin-PP1 and Cyclin-B-CDK1 pathways protects chromosome-microtubule attachments independent of biorientation
Chromosome instability frequently occurs due to issues with chromosome-microtubule attachments. Here the authors show that the Astrin-PP1 and Cyclin-B-CDK1 pathways counteract each other to protect chromosome-microtubule attachments independent of biorientation.
- Xinhong Song
- , Duccio Conti
- & Viji M. Draviam
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CENP-V is required for proper chromosome segregation through interaction with spindle microtubules in mouse oocytes
Chromosome segregation is essential to avoid aneuploidy, yet in mammalian oocytes it progressively fails in an age-dependent manner. Here the authors identify CENP-V as a microtubule binding and bundling protein crucial to faithful oocyte meiosis, and present Cenp-V−/− oocytes as revealing age-dependent weakening of the spindle assembly checkpoint.
- Dalileh Nabi
- , Hauke Drechsler
- & Mariola Chacón
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Epigenetic modifications affect the rate of spontaneous mutations in a pathogenic fungus
While a correlation between epigenetic modifications and mutation rates has been observed, experimental evidence of causality is limited. Here the authors measure the mutation rate in fungal mutants lacking histone modifications and confirm experimentally a causal effect of epigenetic modifications on mutation rates.
- Michael Habig
- , Cecile Lorrain
- & Eva H. Stukenbrock
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Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing
A possible undesired outcome of CRISPR-Cas9 germline editing is unwanted karyotype alterations. Here the authors track aberrations through three divisions of embryonic development following Cas9 editing.
- Stamatis Papathanasiou
- , Styliani Markoulaki
- & David Pellman
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| Open Access
Rad27 and Exo1 function in different excision pathways for mismatch repair in Saccharomyces cerevisiae
Defects in DNA mismatch repair (MMR) have been linked to inherited and sporadic cancers. Here the authors demonstrate that the DNA repair protein Rad27 (human FEN1) functions in one of three redundant mispair excision pathways, where its flap endonuclease activity catalyzes mispair excision.
- Felipe A. Calil
- , Bin-Zhong Li
- & Richard D. Kolodner
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| Open Access
Systems approaches identify the consequences of monosomy in somatic human cells
The mechanisms that allow cancer cells to survive with monosomies are poorly understood. Here the authors analyse p53-deficient monosomic cell lines using transcriptomics and proteomics, and find that impaired ribosome biogenesis and p53 downregulation are associated with sustained monosomies.
- Narendra Kumar Chunduri
- , Paul Menges
- & Zuzana Storchova
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| Open Access
USP11 controls R-loops by regulating senataxin proteostasis
DNA:RNA hybrids (R-loops) are products of transcription that impact genome integrity and gene expression. Here the authors reveal a mechanism for regulating R-loops in a ubiquitination-dependent manner controlled by the activities of USP11 and KEAP1
- Mateusz Jurga
- , Arwa A. Abugable
- & Sherif F. El-Khamisy
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Article
| Open Access
Dpb4 promotes resection of DNA double-strand breaks and checkpoint activation by acting in two different protein complexes
The histone folding protein Dpb4 forms histone-like dimers within the ISW2 complex and the Pol ε complex in S. cerevisiae. Here the authors reveal insights into two distinct functions that Dpb4 exerts at DSBs depending on its interactors.
- Erika Casari
- , Elisa Gobbini
- & Maria Pia Longhese
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Article
| Open Access
Harmful R-loops are prevented via different cell cycle-specific mechanisms
Different factors protect cells from harmful R-loops, but the way these are formed is still unclear. Authors show here that R-loops form co-transcriptionally by different manners and cells possess specialized mechanisms to prevent them in each case, a major mechanism being independent of replication and another one being linked to replication.
- Marta San Martin-Alonso
- , María E. Soler-Oliva
- & Andrés Aguilera
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Article
| Open Access
GIGYF1 loss of function is associated with clonal mosaicism and adverse metabolic health
Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.
- Yajie Zhao
- , Stasa Stankovic
- & John R. B. Perry
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| Open Access
Comprehensive identification of transposable element insertions using multiple sequencing technologies
Identification of transposable element (TE) insertions from whole genome sequencing data remains challenging. Here the authors developed a comprehensive TE insertion detection algorithm xTea that can be applied to both short-read and long-read sequencing data.
- Chong Chu
- , Rebeca Borges-Monroy
- & Peter J. Park
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| Open Access
Inhibition of MRN activity by a telomere protein motif
Telomeres suppress the DNA damage response at chromosome ends. Here the authors show that in budding yeast the activity of the MRX complex in DNA repair and DNA damage signaling is inhibited by telomeric protein Rif2 via a short motif at the N-terminus.
- Freddy Khayat
- , Elda Cannavo
- & Alessandro Bianchi
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| Open Access
UPF1 promotes the formation of R loops to stimulate DNA double-strand break repair
R loops are formed when single-stranded RNA anneals to one strand of DNA, forming three-stranded structures containing DNA-RNA hybrids and the displaced non-template single-stranded DNA. Here the authors reveal that the DNA:RNA helicase UPF1 plays a role in promoting R loops formation at telomeric double strand breaks to stimulate DNA resection and repair.
- Greg H. P. Ngo
- , Julia W. Grimstead
- & Duncan M. Baird
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| Open Access
BRCA1 binds TERRA RNA and suppresses R-Loop-based telomeric DNA damage
BRCA1-mediated resolution of R-loops has previously been described. Here the authors reveal a functional association of BRCA1 with TERRA RNA at telomeres, which develops in an R-loop-, and a cell cycle-dependent manner.
- Jekaterina Vohhodina
- , Liana J. Goehring
- & David M. Livingston
Linear interaction between replication and transcription shapes DNA break dynamics at recurrent DNA break Clusters