Holliday Junction Resolution and Genome Maintenance

Homologous recombination is central to the repair of DNA double-strand breaks and the rescue of stalled replication forks. A pivotal intermediate in this process is the Holliday junction, a four-armed DNA structure linking sister chromatids or homologous chromosomes. Accurate resolution of these junctions by specialised nucleases and resolvases ensures faithful chromosome segregation, prevents deleterious crossovers and maintains genome integrity. A coordinated network of enzymes recognises and cleaves branched DNA, while cell-cycle kinases and spatial regulation confine resolvase activity to mitosis, avoiding inappropriate cleavage during replication. The timely disengagement of recombination intermediates underpins genomic stability, mitigates loss of heterozygosity and safeguards against chromosomal aneuploidy. Insights into the biochemical mechanisms of junction cleavage and the interplay with replication stress responses have revealed new targets for therapeutic intervention in diseases marked by genome instability.

Research from Nature Portfolio

Studies of cells lacking the tumour suppressor BRCA2 have shown that the MUS81 endonuclease is indispensable for rescuing under-replicated regions in mitosis. In the absence of BRCA2, stalled forks persist into mitosis, leading to chromosomal bridges and segregation errors. Activation of MUS81 at mitotic entry promotes compensatory DNA synthesis and the resolution of DNA interlinks, thus preserving cell viability and suggesting a therapeutic window for selective inhibition of MUS81 in BRCA-deficient tumours.

The human Holliday junction resolvase GEN1 is subject to strict spatial control via nuclear exclusion. A dedicated export signal prevents GEN1 from accessing nuclear DNA until nuclear envelope breakdown in mitosis. Artificial retention of GEN1 in the nucleus accelerates resolution of recombination intermediates but elevates crossover formation, highlighting the importance of temporal restriction in balancing crossover and non-crossover repair pathways and in preventing genomic rearrangements.

Holliday Junction Resolution and Genome Maintenance publication trend

The graph below shows the total number of articles in holliday junction resolution and genome maintenance across all publications each year (not limited to Nature Index journals).

Technical terms

Holliday junction: A four-way DNA structure formed during homologous recombination linking two DNA duplexes.

Endonuclease: An enzyme that cleaves the phosphodiester backbone of DNA at internal sites.

Resolvase: A specialised endonuclease that recognises and cleaves Holliday junctions to separate linked DNA molecules.

Replication fork: The Y-shaped structure where DNA strands are unwound and synthesised during replication.

Recombination intermediate: A transient DNA structure, such as a Holliday junction, formed during homologous recombination.

References

1. Biochemical and mechanistic analysis of the cleavage of branched DNA by human ANKLE1. Nucleic Acids Research (2023).
2. The SMX DNA Repair Tri-nuclease. Molecular Cell (2017).
3. MUS81 nuclease activity is essential for replication stress tolerance and chromosome segregation in BRCA2-deficient cells. Nature Communications (2017).
4. Spatial control of the GEN1 Holliday junction resolvase ensures genome stability. Nature Communications (2014).