DNA damage and repair articles within Nature Communications

Featured

• Article
  08 April 2024 | Open Access

  p53 promotes revival stem cells in the regenerating intestine after severe radiation injury

  The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.

  • Clara Morral
  • , Arshad Ayyaz
  •  & David G. Kirsch

• Article
  05 April 2024 | 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

• Article
  03 April 2024 | Open Access

  Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination

  The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.

  • Lorenzo Galanti
  • , Martina Peritore
  •  & Boris Pfander

• Article
  02 April 2024 | Open Access

  PARP2 promotes Break Induced Replication-mediated telomere fragility in response to replication stress

  Here the authors show that PARP2 drives telomere fragility by orchestrating the Break-induced replication (BIR) pathway. This promotes DNA end resection and DNA synthesis via the regulation of POLD3.

  • Daniela Muoio
  • , Natalie Laspata
  •  & Elise Fouquerel

• Article
  28 March 2024 | Open Access

  Mitochondrial H₂O₂ release does not directly cause damage to chromosomal DNA

  Nuclear DNA damage downstream of mitochondrial ROS is often cited to contribute to cancer initiation and aging. However, here the authors show that although H₂O₂ induces DNA mutations when produced near DNA, it does not when released by mitochondria.

  • Daan M. K. van Soest
  • , Paulien E. Polderman
  •  & Tobias B. Dansen

• Article
  27 March 2024 | Open Access

  Real-time monitoring of replication errors’ fate reveals the origin and dynamics of spontaneous mutations

  An interdisciplinary approach following replication errors in Escherichia coli unveils that many spontaneous mutations originate from inefficient repair, and that repair capacity is variable between single cells within a bacterial population.

  • Chiara Enrico Bena
  • , Jean Ollion
  •  & Marina Elez

• Article
  23 March 2024 | Open Access

  Functional screening in human HSPCs identifies optimized protein-based enhancers of Homology Directed Repair

  Here the authors describe a functional screening platform in human stem cells to identify and optimize protein-based gene editing additives that increase homologous directed recombination and have potential to improve gene therapy workflows.

  • Juan A. Perez-Bermejo
  • , Oghene Efagene
  •  & Kristen L. Seim

• Article
  23 March 2024 | Open Access

  Developmental progression of DNA double-strand break repair deciphered by a single-allele resolution mutation classifier

  DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Here, authors develop ICP for deciphering somatic DSB repair patterns in multicellular organisms and discover developmental regulation in flies and mosquitoes, enabling tracking of mutant alleles and interhomolog copying of gene cassettes.

  • Zhiqian Li
  • , Lang You
  •  & Ethan Bier

• Article
  21 March 2024 | Open Access

  p53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice

  DNA repair deficiency can cause tissue-specific phenotypes in humans and mice. Here, the authors find that p53 drives different, but tissue-specific responses despite the same defect in DNA repair. p53 drives blood stem cell loss but restrains liver polyploidisation in the absence of Ercc1.

  • Ross J. Hill
  • , Nazareno Bona
  •  & Gerry P. Crossan

• Article
  12 March 2024 | Open Access

  ZNF827 is a single-stranded DNA binding protein that regulates the ATR-CHK1 DNA damage response pathway

  Here, the authors characterise the zinc finger protein ZNF827 as a single stranded DNA binding protein that accumulates at stalled replication forks to activate the ATR-CHK1 pathway and engage homologous-recombination mediated DNA repair.

  • Sile F. Yang
  • , Christopher B. Nelson
  •  & Hilda A. Pickett

• Article
  08 March 2024 | Open Access

  GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer

  GRB2 is known for its role in Receptor Tyrosine Kinase and RAS signaling. Here the authors unveil a GRB2 function and mechanism for DNA replication fork protection. GRB2 alleviates oncogenic replication stress, and in doing so, averts cancer immune destruction by inhibiting cGAS/STING and pro-inflammatory cytokine production.

  • Zu Ye
  • , Shengfeng Xu
  •  & Zamal Ahmed

• Article
  07 March 2024 | Open Access

  Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes

  FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.

  • Sowmiya Palani
  • , Yuka Machida
  •  & Yuichi J. Machida

• Article
  04 March 2024 | Open Access

  Trans-lesion synthesis and mismatch repair pathway crosstalk defines chemoresistance and hypermutation mechanisms in glioblastoma

  Glioblastoma (GBM) is refractory to the chemotherapeutic genotoxin temozolomide (TMZ). Here, the authors show that GBM cells deploy RAD18-mediated Trans-Lesion Synthesis to promote error-free repair of TMZ-induced O⁶mG DNA lesions and avert lethality.

  • Xing Cheng
  • , Jing An
  •  & Yang Yang

• Article
  29 February 2024 | Open Access

  The Deinococcus protease PprI senses DNA damage by directly interacting with single-stranded DNA

  Lu et al. show that single-stranded DNA produced as a result of DNA damage may directly activate PprI in Deinococcus species, triggering the DNA damage response.

  • Huizhi Lu
  • , Zijing Chen
  •  & Yuejin Hua

• Article
  21 February 2024 | Open Access

  Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair

  Aberrant expression of Synaptonemal complex protein 2 (SYCP2) in breast and ovarian cancers is associated with resistance to drugs targeting the DNA damage response. Here the authors show that SYCP2 confers drug resistance by promoting R-loop formation during transcription-coupled homologous recombination.

  • Yumin Wang
  • , Boya Gao
  •  & Li Lan

• Article
  15 February 2024 | Open Access

  Trabectedin derails transcription-coupled nucleotide excision repair to induce DNA breaks in highly transcribed genes

  The antitumor drug trabectedin is more toxic to DNA-repair-proficient cells. Here the authors show that this is caused by persistent DNA breaks induced from an abortive repair reaction and develop “TRABI-Seq” to map the breaks to transcribed regions of the genome. Trabectedin may thus be used as a diagnostic and therapeutic in precision oncology.

  • Kook Son
  • , Vakil Takhaveev
  •  & Orlando D. Schärer

• Article
  10 February 2024 | Open Access

  Structural role for DNA Ligase IV in promoting the fidelity of non-homologous end joining

  Nonhomologous end joining (NHEJ), the primary pathway of vertebrate DNA double strand-break (DSB) repair, directly re-ligates broken DNA ends with minimal errors. In this study, the authors identify structural interactions of the NHEJ-specific DNA Ligase IV (Lig4) that prioritize ligation and promote NHEJ fidelity.

  • Benjamin M. Stinson
  • , Sean M. Carney
  •  & Joseph J. Loparo

• Article
  29 January 2024 | Open Access

  FLIP(C1orf112)-FIGNL1 complex regulates RAD51 chromatin association to promote viability after replication stress

  Recombination is essential for life. Here, the authors characterize FLIP as a novel regulator of the key recombination protein RAD51’s functions. FLIP loss caused marked sensitivity to DNA damage, increased DNA breakage and defective replication.

  • Jessica D. Tischler
  • , Hiroshi Tsuchida
  •  & Richard O. Adeyemi

• Article
  08 January 2024 | Open Access

  PSIP1/LEDGF reduces R-loops at transcription sites to maintain genome integrity

  R-loop accumulation at transcription sites poses a persistent threat to genome integrity. Here the authors demonstrate a role for PSIP1/LEDGF protein in reducing R-loop levels at the site of transcription and preventing transcription replication conflict to maintain genome integrity.

  • Sundarraj Jayakumar
  • , Manthan Patel
  •  & Madapura M. Pradeepa

• Article
  02 January 2024 | Open Access

  Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response

  Here the authors show that gain-of-function mutant p53s predispose cells to chromosomal instability by targeting MCMs, leading to activation of a cGAS-STING-non-canonical NF-κB signaling that promotes tumor metastasis and immunosuppression.

  • Mei Zhao
  • , Tianxiao Wang
  •  & Ge Zhou

• Article
  18 December 2023 | Open Access

  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

• Article
  14 December 2023 | Open Access

  Profiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCF^β-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1

  Using Xenopus egg extracts, the authors developed a mass spectrometry method (UBIMAX) to identify proteins ubiquitylated in response to defined DNA lesions. Highlighting UBIMAX’s versatility, they describe the ubiquitylation of the actin regulator Dbn1 in response to DNA double-strand breaks.

  • Camilla S. Colding-Christensen
  • , Ellen S. Kakulidis
  •  & Michael L. Nielsen

• Article
  12 December 2023 | Open Access

  Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation

  Zhen and colleagues show that nuclear cGAS represses L1 retrotransposition to stabilize the genome by enhancing the interaction between ORF2p and the E3 ligase TRIM41 upon DNA damage, which leads to the ubiquitination and degradation of ORF2p.

  • Zhengyi Zhen
  • , Yu Chen
  •  & Zhiyong Mao

• Article
  29 November 2023 | Open Access

  Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting

  What underlies the synthetic lethality between BRCA1/2 or 53BP1 loss and Polθ loss is unclear. Here, the authors show that RPA-RAD52-MRE11 drive lethality when Polθ is absent in these cells. In BRCA1/2-deficient cells, sensitivity to Polθ inhibition additionally depends on the inhibited protein.

  • George E. Ronson
  • , Katarzyna Starowicz
  •  & Joanna R. Morris

• Article
  28 November 2023 | Open Access

  Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity

  How nuclear architecture assists the replication stress response is still largely unknown. Here the authors show that nuclear actin polymerization rapidly extends upon mild DNA damage. By limiting Primpol activity, this response mediates fork slowing and reversal, protecting chromosome stability.

  • Maria Dilia Palumbieri
  • , Chiara Merigliano
  •  & Massimo Lopes

• Article
  22 November 2023 | Open Access

  A dual role of RBM42 in modulating splicing and translation of CDKN1A/p21 during DNA damage response

  Here the authors show a function of RBM42 in regulating splicing and translation of the p53-target gene CDKN1A/p21. This makes RBM42 an RNA-binding protein that links splicing and translation to fine-tune gene expression during DNA damage.

  • Bella M. Ben-Oz
  • , Feras E. Machour
  •  & Nabieh Ayoub

• Article
  21 November 2023 | Open Access

  Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

  It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.

  • Sarasa Isobe
  • , Ramesh V. Nair
  •  & Marlene Rabinovitch

• Article
  15 November 2023 | Open Access

  Nucleolar reorganization after cellular stress is orchestrated by SMN shuttling between nuclear compartments

  DNA damage causes a major reorganization of the nucleolus. Here, the authors find that this structural restoration depends on the shuttling of the protein SMN from the Cajal bodies to the nucleolus, which requires coilin and PRMT1.

  • Shaqraa Musawi
  • , Lise-Marie Donnio
  •  & Giuseppina Giglia-Mari

• Article
  09 November 2023 | Open Access

  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

• Article
  04 November 2023 | Open Access

  Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs

  ALT cells use an alternative lengthening mechanism of telomeres and bear telomeric DNA damage with increased levels of damage-induced long non-coding RNA. Here the AUs show that antisense oligonucleotides (ASO) targeting such RNAs can induce ALT cancer cells selective cell death.

  • Ilaria Rosso
  • , Corey Jones-Weinert
  •  & Fabrizio d’Adda di Fagagna

• Article
  02 November 2023 | Open Access

  Structural basis for stabilisation of the RAD51 nucleoprotein filament by BRCA2

  Here the authors report the cryoEM structure of the RAD51 nucleoprotein filament bound to the C-terminal TR2 domain of BRCA2. The structure explains how BRCA2 stabilises the filament and uncovers a conserved mechanism of filament binding by recombination mediators.

  • Robert Appleby
  • , Luay Joudeh
  •  & Luca Pellegrini

• Article
  23 October 2023 | Open Access

  UV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence

  Senescence can be activated in a DNA damage-dependent and -independent manner. Here the authors reveal in cell lines that recruitment of the factor ZRF1 at G4 DNA structures can prevents UV-induced senescence.

  • Alessio De Magis
  • , Michaela Limmer
  •  & Katrin Paeschke

• Article
  30 September 2023 | Open Access

  The RNA m5C modification in R-loops as an off switch of Alt-NHEJ

  Here the authors show that DNA damage induced RNA m5C in R-loops competes with PARP1- mediated PARylation in transcribed genomes to promote cell survival which could be targeted be in cancer therapy.

  • Haibo Yang
  • , Emily M. Lachtara
  •  & Li Lan

• Article
  22 September 2023 | Open Access

  SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation

  The authors show that the SUMO protease SENP6 plays an essential role in maintaining genome integrity by disassembling SUMO2/3 polymers from DNA damage response proteins, thereby preventing their trapping at sites of DNA damage and in nuclear condensates.

  • Laura A. Claessens
  • , Matty Verlaan-de Vries
  •  & Alfred C. O. Vertegaal

• Article
  16 September 2023 | Open Access

  Genome-wide analysis of DNA-PK-bound MRN cleavage products supports a sequential model of DSB repair pathway choice

  Deshpande et al show that MRN nuclease-dependent processing of DNA ends in human cells occurs at sites bound by DNA-PK. Chromatin immunoprecipitation analysis of DNA-PK, MRN, and CtIP supports a sequential model of pathway choice.

  • Rajashree A. Deshpande
  • , Alberto Marin-Gonzalez
  •  & Tanya T. Paull

• Article
  15 September 2023 | Open Access

  Inducing multiple nicks promotes interhomolog homologous recombination to correct heterozygous mutations in somatic cells

  Gene editing is still hampered by unintended genomic alterations. Here the authors propose a method for correcting heterozygous mutations that employs multiple nicks induced by Cas9 nickase and the homologous chromosome as an endogenous repair template (NICER): this rarely induces unintended genomic alterations.

  • Akiko Tomita
  • , Hiroyuki Sasanuma
  •  & Shinichiro Nakada

• Article
  25 August 2023 | Open Access

  A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells

  Here the authors study how BRCA2 mutations affect mammary epithelial subpopulations. They report that Brca2^mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2^mut/WT HR- luminal cells.

  • Maryam Ghaderi Najafabadi
  • , G. Kenneth Gray
  •  & Mona Shehata

• Article
  24 August 2023 | Open Access

  RNAPII-dependent ATM signaling at collisions with replication forks

  Deregulation of transcription by oncogenes leads to collisions of RNA Polymerase II (RNAPII) with DNA replication machinery (transcription-replication conflicts, TRCs). This study shows that RNAPII activates ATM kinase at TRCs providing a mechanism for replication fork stalling and ATM activation at TRCs.

  • Elias Einig
  • , Chao Jin
  •  & Nikita Popov

• Article
  23 August 2023 | Open Access

  Trim33 masks a non-transcriptional function of E2f4 in replication fork progression

  Here the authors show that under replicative stress the E2f4 transcription factor recruits the Recql DNA helicase to facilitate DNA replication. The Trim33 ubiquitin ligase targets E2f4 to limit its interactions with Recql and chromatin.

  • Vanessa Rousseau
  • , Elias Einig
  •  & Nikita Popov

• Article
  22 August 2023 | Open Access

  Histone H3 serine-57 is a CHK1 substrate whose phosphorylation affects DNA repair

  Histone post-translational modifications control several fundamental processes on DNA. Here, the authors describe a conserved phosphorylation of histone H3 on the globular core and show that it loosens the nucleosome and regulates DNA repair.

  • Nikolaos Parisis
  • , Pablo D. Dans
  •  & Daniel Fisher

• Article
  21 August 2023 | Open Access

  TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells

  The TRAIP E3 ubiquitin ligase is essential for genome integrity, mutations lead to primordial dwarfism in patients. Here, the authors show that TRAIP degradation in S-phase, results in cell arrest due to DNA damage caused by replication-transcription conflicts.

  • Shaun Scaramuzza
  • , Rebecca M. Jones
  •  & Agnieszka Gambus

• Article
  17 August 2023 | Open Access

  A RAD51–ADP double filament structure unveils the mechanism of filament dynamics in homologous recombination

  RAD51 filaments are essential for eukaryotic homologous recombination. This study shows the cryo-EM structure of an ADP-bound RAD51 double-filament that wraps around ssDNA revealing a stepwise collapsing mechanism for the transition between the ATP/ADP-bound filament intermediates.

  • Shih-Chi Luo
  • , Min-Chi Yeh
  •  & Meng-Chiao Ho

• Article
  17 August 2023 | Open Access

  C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption

  Here the authors identify that C16orf72 regulates BRCA1/Senataxin to promote replication fork recovery. These proteins act together in a pathway parallel to PARP1 to suppress R-loop accumulation in response to replication stress and confer resistance to PARP inhibitors.

  • Abhishek Bharadwaj Sharma
  • , Muhammad Khairul Ramlee
  •  & Nicholas D. Lakin

• Article
  14 August 2023 | Open Access

  Simultaneous inhibition of DNA-PK and Polϴ improves integration efficiency and precision of genome editing

  Low efficiency of target DNA integration remains a challenge in genome engineering. Here the authors perform large-scale compound library and genetic screens to identify targets that enhance gene editing: they see that combined DNA-PK and Polϴ inhibition with potent compounds increases editing efficiency and precision.

  • Sandra Wimberger
  • , Nina Akrap
  •  & Marcello Maresca

• Article
  24 July 2023 | Open Access

  RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles

  In this study, the authors present structures and functional analyses for the RAD51C-XRCC3 tumor suppressor complex, providing insights into recurrent mutations in cancer and Fanconi Anemia patients that uncover distinct DNA replication fork protection, restart and reversal regions.

  • Michael A. Longo
  • , Sunetra Roy
  •  & Katharina Schlacher

• Article
  20 July 2023 | Open Access

  Age-related self-DNA accumulation may accelerate arthritis in rats and in human rheumatoid arthritis

  The incidence of rheumatoid arthritis (RA) and accumulation of circulating free (cf) DNA increase with age but it is unknown whether DNA fragments cause joint inflammation. Here authors show that cf DNA levels are higher in RA patients and that in a rat adjuvant-induced arthritis model, the exonuclease TREX1 suppresses synovial inflammation via promoting the degradation of cf DNA and inhibiting a senescence-like cellular state.

  • Wei-Dan Luo
  • , Yu-Ping Wang
  •  & Vincent Kam Wai Wong

• Article
  18 July 2023 | Open Access

  Regulation of Rad52-dependent replication fork recovery through serine ADP-ribosylation of PolD3

  Here the authors identify that PARP1 maintains genome integrity by regulating replication fork recovery by break-induced replication. Mechanistically, this is achieved through MRE11-dependent PARP1 activation and site-specific ADP-ribosylation of PolD3.

  • Frederick Richards
  • , Marta J. Llorca-Cardenosa
  •  & Nicholas D. Lakin

• Article
  15 July 2023 | Open Access

  Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

  It is critical to understand what drives the progression of oesophageal adenocarcinoma (OAC) from a pre-cancerous state. Here, the authors use whole-genome sequencing to characterise the mutational processes and drivers of OAC progression from Barrett’s Oesophagus, as well as their prognostic associations.

  • Sujath Abbas
  • , Oriol Pich
  •  & Maria Secrier

• Article
  10 July 2023 | Open Access

  Cell cycle arrest and p53 prevent ON-target megabase-scale rearrangements induced by CRISPR-Cas9

  ON-target genotoxicity in gene editing is generally underestimated. Here the authors report Fluorescence-Assisted Megabase-scale Rearrangements Detection (FAMReD) systems to detect and characterize rare large loss of heterozygosity: they show that ON-target genotoxicity can be prevented by p53 and cell cycle arrest.

  • G. Cullot
  • , J. Boutin
  •  & A. Bedel

• Article
  01 July 2023 | Open Access

  ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair

  Due to the naturally dense packing of the genome, DNA repair factors encounter a topologically very intricate cellular context. We describe how the human ASH1L protein navigates excision repair factors to accelerate their search for DNA lesions.

  • Corina Maritz
  • , Reihaneh Khaleghi
  •  & Hanspeter Naegeli