Search

Iron dysregulation is a hallmark of many human diseases and cancers. In this study, the authors show that iron depletion, overload, or improper storage drive templated insertions at chromosome breaks, a class of events that are common yet poorly understood in cancer.

HiScanner, a tool for identification of copy number alterations from single cell whole-genome sequencing data, uncovers cell-type-specific somatic mosaicism in human brain and offers a way to track clonal evolution at the single cell resolution.

Progerin, a truncated version of lamin A, causes Hutchinson–Gilford progeria syndrome characterized by premature aging and cardiovascular complications. Here the authors show that the most common progeria-causing mutation, LMNA c.1824C>T, is a somatic mutation in arteries from patients with chronic kidney disease, and that clonal propagation of the mutation in the vascular wall results in vascular aging phenotypes in mice.

SAVANA is a tool to detect somatic structural variants and copy number aberrations using long-read sequencing data, offering high sensitivity, specificity and compatibility with or without germline controls.

Studies on the essentiality of Ku in human cells reveal that Ku interacts with diverse double-stranded RNA molecules, including antisense Alu, and enables tolerance of Alu sequence expansion in primates.

Hutchinson-Gilford Progeria Syndrome is characterized by premature aging with cardiovascular disease being the main cause of death. Here the authors show that inhibition of the NAT10 enzyme enhances cardiac function and fitness, and reduces age-related phenotypes in a mouse model of premature aging.

Mackey et al report the transcriptional signature and phenotypic features of aneuploid Candida albicans strains which impact infection and susceptibility to environmental stimuli.

The DNA breaks that initiate recombination during meiosis are resected by nucleases, but the mechanism of this resection in mammals is poorly understood. Here, the authors examine the roles of the MRE11-RAD50- NBS1 complex in beginning and extending resection during meiosis in male mice.

Here, Zerio et al. use cryo-electron microscopy to show how the helicase ___domain of DNA polymerase θ aligns broken DNA strands by matching short sequences, a process linked to cancer. These findings may guide future therapies targeting error-prone DNA repair.

Structural variants (SV) can accumulate in repeat-rich parts of the genome and transform them in unexpected ways. Here, with their new assembly-based genotyper (NAHRwhals), the authors verify multi-step SVs in 37 human loci and identify alleles at risk for copy-number variation.

Aberrant oncogene expression can cause replication stress leading to chromosomal breaks. Here the authors map the chromosomal break loci induced by two different oncogenes and by a replication inhibitor, and show that each treatment induces a unique pattern of breaks in the same cell type.

The molecular basis of the preferential metastasis to specific organs in colorectal cancer (CRC) remains to be explored. Here, the authors identify the cytogenetic events that favor metastatic colonization at specific sites by studying cohorts of primary CRCs and metastases.

How repair of DNA interstrand crosslinks contributes to mutagenesis is not understood. Here, the authors identify two mutagenic repair pathways in C. elegans: FAN1-mediated translesion synthesis causing SNVs, and POLQ-mediated end joining leading to deletions. They also uncover a role for TRAIP.

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.

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.

Transcription termination or pausing during DNA replication in bacteria and humans results in DNA damage with exposed 3′ single-stranded DNA ends and mutations.

Cancer mutational signatures have been associated with defects in genome maintenance pathways. Here the authors, by using a worm germline mutagenesis model defective of human orthologue BRCA-1, identify polymerase theta-mediated end-joining (TMEJ) as causing the BRCAness mutational signature.

Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.

A conserved feature of metazoan meiosis is that it occurs in a syncytium. Here, the authors show that intercellular bridges that connect germ cells in a syncytium are critical for ensuring proper meiotic progression and fertility in male mice.

In humans, ADPKD can develop from “second hit” mutations in the PKD1 gene. Here, the authors show that human PKD1 contains guanine quadruplex structures that cause mutagenic double stranded breaks.

The DNA damage checkpoint needs to be turned off to allow cellular recovery from genotoxic exposure. Here, the authors report that the scaffold proteins Rtt107 and Mms22 and their associated ubiquitin ligase enable this downregulation and reduces the level of a key checkpoint mediator Rad9.

The germline maintains unstable essential ribosomal DNA (rDNA) repeats to ensure each generation inherits a functional genome, yet it’s unclear how this activity is controlled. Here, the authors find the insulin receptor governs germline rDNA maintenance in response to genetic and dietary cues.

Single-cell replication timing (scRT) studies in cancer are challenging due to genomic heterogeneity. Here, the authors develop MnM, a machine learning tool that can provide heterogeneity-resolved scRT profiles, and apply it to a large single-cell dataset that includes tumours, cell lines, and patient-derived xenografts.

Here the authors show that the DNA helicase WRN ‘s interaction with the single stranded DNA binding protein RPA is regulated through specific phosphorylation by Casein Kinase 2. This regulation is critical for resolving DNA replication stress caused by G-quadruplexes.

MSX1 phase separation are associated with cleft palate. Here the authors show that MSX1 phase separation, triggered by its N-terminal intrinsically disordered region and regulated by PRMT1-catalyzed methylation, is a vertebrate-conserved mechanism for embryonic palatal development.

Whereas the toxic effects of ethanol are well-documented, the underlying mechanism is obscure. This study uses the eukaryotic model S. cerevisiae to reveal how exposure to sublethal ethanol concentrations causes DNA replication stress and an increased mutation rate.

DNA repeats can lengthen or shorten during their replication, which may lead to a human disease. Here, the authors discovered that an essential replication protein, Mcm10, counteracts instability of GAA repeats, implicated in Friedreich’s ataxia, as well as death of repeat-containing cells.

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.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

Systemic sclerosis patients often develop cancer, but why this happens is poorly understood. Here, the authors propose a possible mechanism linking these diseases by showing increased somatic mutations and genome instability in systemic sclerosis.

DNA ligase 1 finalizes nuclear DNA replication by accurately sealing nicks generated during Okazaki Fragment Maturation. Here, Williams et al employ a low fidelity DNA ligase 1 variant to study mutation rates and specificity across the yeast genome

Development of a dual-fluorescent reporter system allows rapid quantification of diverse genomic copy number changes that arise in Candida albicans during adaptation to antifungal drugs.

SWR-C and its substrate the histone variant Htz1 are considered important for genome maintenance. Here the authors reveal that SWR-C/Htz1 plays a critical role during replication stress caused by absence of the replication fork progression proteins Mrc1/Tof1/Csm3.

Here, the authors have integrated genome-wide association data with functional genomics data relevant to the kidney and performed in vitro and in vivo experiments which support TET2 as a kidney disease risk gene.

Yang et al. show that transcription–replication collisions lead to large tandem duplications, which are frequent in female-enriched, upper gastrointestinal tract and prostate cancers and are associated with poor survival and mutations in specific genes, such as CDK12.

The mechanisms of nonrecurrent structural variant (SV) formation are poorly understood. Here, the authors sequenced thousands of SV junctions as they formed at common fragile sites in human cell lines to reveal a primary role for DNA polymerase theta-mediated end joining activated during mitosis.

Mitotic errors promote chromosome fragmentation and rearrangements through chromothripsis. Here, the authors identify NHEJ as the primary DSB repair pathway underlying chromothripsis and investigate the kinetics of fragment reassembly across the cell cycle.

CSB deficiency is associated with induction of R-loops and genome instability, impacting long genes linked to neuronal functions in humans. Here the authors provide mechanistic understanding on how mutations in the CSB gene affects RNAPII elongation and genome instability.

The elongation factor Elf1 functions in transcription coupled-nucleotide excision repair (TC-NER), but the mechanism by which yeast Elf1 promotes repair was unclear. Here, the authors show that Elf1 promotes TC-NER by binding TFIIH through a conserved sequence motif in its C-terminal ___domain.

Gene editing induces paternal haploid plants in hexaploid wheat.

Collisions of transcription and replication machineries on the same DNA strand threaten genomic stability. Here, the authors show that RAD52 prevents these collisions by regulating R-loop formation and resolution. RAD52 deficiency leads to increased R-loops, exacerbated collisions, DNA damage, and higher mutational burden in tumors.

In the United States, Black patients have higher rates of cancer mortality, but the sources of such disparities remain poorly understood. Here, the authors analyze genomic data from large-scale patient cohorts and find that cancers from self-reported Black patients are significantly more likely to exhibit whole genome duplications; they also explore a potential link to environmental exposures.

High-resolution structures of DNA-bound multiprotein Spo11 complexes, the DNA-cleaving ensembles that initiate meiotic recombination, elucidate the structural basis of its DNA-binding specificity and explain recombination initiation patterns in vivo.

In neural progenitor cells, recurrent DNA break clusters (RDCs) occur to genes crucial for brain function. Here the authors find that most RDCs emerge at long-traveling unidirectional replication forks, and often unrelated to R-loops.

The authors elucidate by cryo-EM the mechanism by which DNA polymerases Rev1 and Polζ cooperate in translesion DNA synthesis.