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Chromosomal fragile sites (CFSs) are prone to breakage and thus can cause genomic instability. Hickson and colleagues demonstrate that the MUS81 endonuclease localizes to CFSs and mediates their processing, revealing that CFS cleavage is an active process.

Common fragile sites (CFSs) are difficult-to-replicate regions of eukaryotic genomes that are sensitive to replication stress and that require resolution by the MUS81–EME1 endonuclease to re-initiate POLD3-dependent DNA synthesis in early mitosis; this study defines the specific pathway of events causing the CFS fragility phenotype.

A method that uses a combination of optical trapping, fluorescence microscopy and microfluidics to analyse the internal structure of chromosomes shows that there is a distinct nonlinear stiffening of the chromosome in response to tension.

In recent years, there has been a tremendous advance in our understanding of the cellular functions of individual RecQ helicases. This Review discusses how these proteins might suppress genomic rearrangements, and therefore function as 'caretaker' tumour suppressors.

The FANC and the BLM pathways collaborate during mitosis to prevent micronucleation and chromosome abnormalities.

The physical mechanisms that govern chromosomal viscoelasticity remain elusive. Here the authors combine single-chromosome manipulation and computational methods to show that their collective properties are controlled by the physico-chemical environment.

Analysis of DNA replication fork arrest is challenging due to lack of techniques that induce site-specific replication barriers in eukaryotic chromosomes. Here, Larsen et al. create a novel tool to trigger targeted replication fork pausing by engineering the bacterial Tus–Tersystem into the yeast genome.

During mitosis the translocase PICH binds to ultrafine bridges formed from DNA catenanes that are unresolved by topoisomerase II. In this study, the authors show that PICH stimulates toposiomerase II activity and that they cooperate to resolve these structures.

A combination of cellular and genome-wide mapping approaches reveal that RTEL1 helicase functions with SLX4 to resolve R-loops and G-quadruplex structures that impede DNA replication fork progression in human cells.

The F-box DNA helicase 1 (FBH1) is implicated in suppression of homologous recombination (HR), but the precise mechanism is unclear. Here, the authors show that FBH1 can ubiquitylate RAD51, a central player in HR, and controls the subcellular localization of RAD51.

PICH and Topoisomerase 3a together introduce positive supercoiling into DNA, which could aid efficient sister-chromatid disjunction during mitosis.

Hertz et al. use CRISPR screening to identify genetic vulnerabilities to inhibition of SUMOylation in human cells. They show that SUMO exerts its essential role in cell proliferation via NIP45- and BTRR-PICH-mediated DNA catenane resolution pathways.

In anaphase, any unresolved DNA entanglements between the segregating sister chromatids can give rise to chromatin bridges. Here, the authors present an in vitro single-molecule assay that mimics chromatin under tension, to show that PICH is a tension- and ATP-dependent nucleosome remodeler.

Here the authors probe the cleavage and gate opening of single-stranded DNA by the human topoisomerase TRR using a unique single-molecule strategy to reveal structural plasticity in response to both double-stranded DNA and the helicase BLM.

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.

Single-molecule and biochemistry approaches are used to investigate how ultra-fine DNA bridges, which form between sister chromatids during anaphase, are recognized and processed by cellular factors PICH, BLM, TopoIIIα and RPA.

In fast proliferating embryonic stem cells (ESC) the DNA damage response is activated by mechanisms that are as yet elusive. Here, Ahuja et al.link the DNA damage response to replication stress in mouse ESCs, caused by a short G1 phase, and propose fork remodelling as maintaining genome stability in embryos.

In a short-term study in which hearts from gene-edited pigs were transplanted into two recently deceased human recipients, the hearts were able to function for the duration of the study without signs of rejection and without evidence of pig virus transmission, encouraging further clinical study of cardiac xenotransplantation.

53BP1 is marker of double-strand breaks and accumulates in nuclear foci. These foci are shown to accumulate in G1 at lesions generated by replication stress and may shield lesions from erosion.

A complex substrate containing mobile double Holliday junctions is now used to show that yeast proteins Sgs1 (DNA helicase) and Top3 (topoisomerase) act together to dissolve the junctions and avoid crossing over; the protein Rmi1 stimulates this process.

G-quadruplexes (G4) DNA are DNA structures found throughout the genome previously shown to be bound with high specificity by the RecQ family helicase BLM. Here the authors describe how BLM interacts with G4 DNA in molecular details and propose an integrated model of the cooperative binding between BLM and G4 structures.

The 'dissolvasome', composed of TopIIIα, BLM and RMI proteins, coordinates DNA-helicase and DNA-topoisomerase activities to resolve double Holliday junctions (dHJs) generated during DNA recombination and repair. The first crystal structure of a human TopIIIα–Rmi1 subcomplex provides insights into how topoisomerase is stimulated to promote dHJ decatenation.

Fanconi anaemia, ataxia telangiectasia, Nijmegen breakage syndrome and Bloom syndrome are rare, clinically distinct, chromosome instability syndromes. This Primer describes the understanding of the genetic and molecular basis of these disorders, including the relationship of the defects to the predisposition to cancer.

This Perspective advocates the study of tumour predisposition syndromes as an opportunity to better identify gene–environment interactions that influence cancer risk. Understanding syndrome-associated molecular mechanisms may provide new and more effective ways to prevent exposure-associated cancers in the general population.