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DNA packaging by molecular motors: from bacteriophage to human chromosomes

Abstract

Dense packaging of genomic DNA is crucial for organismal survival, as DNA length always far exceeds the dimensions of the cells that contain it. Organisms, therefore, use sophisticated machineries to package their genomes. These systems range across kingdoms from a single ultra-powerful rotary motor that spools the DNA into a bacteriophage head, to hundreds of thousands of relatively weak molecular motors that coordinate the compaction of mitotic chromosomes in eukaryotic cells. Recent technological advances, such as DNA proximity-based sequencing approaches, polymer modelling and in vitro reconstitution of DNA loop extrusion, have shed light on the biological mechanisms driving DNA organization in different systems. Here, we discuss DNA packaging in bacteriophage, bacteria and eukaryotic cells, which, despite their extreme variation in size, structure and genomic content, all rely on the action of molecular motors to package their genomes.

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Fig. 1: Bacteriophages package their DNA using a single molecular motor.
Fig. 2: Properties of DNA packaging and DNA interacting proteins across scales.
Fig. 3: Organizational features of the bacterial genome are driven by DNA-associated proteins.
Fig. 4: The eukaryotic genome is hierarchically organized by SMC proteins.

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Acknowledgements

The authors thank L. Di Pompeo for the help with preparing of the ribbon diagrams of the condensin holo complex (PBD: 6YVU, Box 3) and the P22 portal protein (PBD: 5JJ1, Fig. 1E); X. Wang and D. Rudner for sharing of the bacterial Hi-C interaction maps (Fig. 3d); J. Gibcus, K. Samejima, S. Abraham and J. Dekker for sharing the improved DT40 Hi-C interaction maps before publication (Fig. 4b) and Johan for assembly of the Hi-C maps; R. Barth and C. Dekker for sharing of the raw condensin loop extrusion data (Fig. 4c); and A. Goloborodko for sharing details of his polymer modelling before publication (Fig. 4e–g). The authors’ work is supported by a Sir Henry Wellcome Postdoctoral Fellowship (215925) to B.P. and a Wellcome Principal Research Fellowship (107022) to W.C.E.

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Glossary

Burst phase

The time that a motor protein is active, during which ATP hydrolysis drives a series of conformational changes.

Chromatin immunoprecipitation

(ChIP). A technique in which antibodies are used to pull down target proteins that are cross-linked to the DNA; sequencing is then used to identify associated (genomic) regions.

Chromosome condensation

The re-organization of chromatin that accompanies the disassembly of interphase chromatin structures and formation of compact mitotic chromosomes.

Contour length

The length of a (DNA) polymer measured when the polymer is fully extended, a condition that never occurs in living cells.

Convergent orientation

Two CTCF binding sites facing each other so that continuous loop extrusion brings them together at the base of the chromatin loop.

DNA compaction

The reduction of the volume occupied by DNA or chromatin, which, in eukaryotes, might be expected to be driven by changes in histone post-translational modifications.

DNA plectonemes

Extended structures in which the DNA double helix is wrapped around itself as a result of DNA supercoiling.

DNA supercoiling

The over-winding or under-winding of DNA.

Dwell phase

The time that a motor protein is waiting, and no ATP-driven conformational changes are occurring.

Entropic repulsion

A force emerging from the fact that overlap of DNA loops is energetically unfavourable, preventing DNA entanglement.

Fluorescence in situ hybridization

(FISH). A fluorescence-microscopy approach that uses fluorescent sequence-specific adapters to visualize the chromosome by base-pairing at a specific genomic location.

Fourier shell model

Spatial frequency analysis of the diffraction patterns to determine spherical shell spacing.

Lengthwise compaction

An overestimate of the true compaction ratio obtained by dividing the DNA contour length (its maximum linear extension) by the length of the major axis of the enclosing compartment.

Loop extrusion

The SMC-driven formation of a DNA loop, which involves incorporation of adjacent DNA into a loop while keeping the two ends together at the base.

Macrodomains

Megabase-sized chromosomal regions that are spatially isolated.

Molecular dynamics

A computational technique to capture the positioning of a set of molecules over time.

Multiplexed error-robust fluorescence in situ hybridization

(MERFISH). A fluorescence-microscopy approach that builds up a structural map of the DNA, using the localization of large numbers of fluorescent sequence-specific adapters that are sequentially added, imaged and removed during the experiment.

Nucleoid

Region of the bacterial cell containing the chromosome composed of DNA and associated proteins.

Phase separation

The emergence of two or more separate phases from a mixture such as oil and water, or the cytoplasm.

Stall force

The opposing force at which a motor protein stops moving or translocating cargo (in this case, DNA or chromatin).

Topologically associated domains

(TADs). Regions of clustered loops of 105–106 base pairs extruded by cohesin that are localized by cohesin binding to CCCTC-binding factor (CTCF) at genomic positions defined by convergent CTCF binding sites.

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Prevo, B., Earnshaw, W.C. DNA packaging by molecular motors: from bacteriophage to human chromosomes. Nat Rev Genet (2024). https://doi.org/10.1038/s41576-024-00740-y

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