Homologous Recombination and Non-Homologous End Joining

A double-strand break severs both strands of the DNA helix and, if misrepaired, can cause loss of genetic material or chromosomal rearrangement. Cells repair such breaks by two main routes: homologous recombination, which copies sequence from an intact homologous template and is largely error-free, and non-homologous end joining, which directly rejoins the broken ends and can act at any time but may introduce small changes at the junction.

Definition

Homologous recombination (HR) repairs double-strand breaks by using a homologous DNA sequence, typically the sister chromatid, as a template for accurate resynthesis, whereas non-homologous end joining (NHEJ) repairs them by directly ligating the broken ends with little or no requirement for sequence homology.

Scope

This entry compares the two double-strand break repair pathways, including the steps of each, the role of end resection in directing pathway choice, and the influence of cell-cycle phase on which pathway predominates. It is a mechanistic reference and does not provide clinical guidance.

Core questions

• How does each pathway repair a double-strand break?
• What determines whether a break is repaired by recombination or by end joining?
• Why is homologous recombination generally accurate and end joining sometimes not?
• How does the cell cycle influence pathway choice?

Key concepts

• Double-strand break
• End resection
• Homologous template (sister chromatid)
• Strand invasion
• Direct end ligation
• Cell-cycle-dependent pathway choice
• Error-free versus error-prone repair
• Chromosomal rearrangement

Mechanisms

Pathway choice is set largely by whether the broken ends are resected. In non-homologous end joining, the ends are bound and processed minimally and then directly ligated; Lieber describes how this pathway can operate throughout the cell cycle and is the dominant route in mammalian cells, at the cost of occasionally altering the sequence at the junction. In homologous recombination, the ends are resected to expose single-stranded DNA, which then invades a homologous template, usually the sister chromatid, to prime accurate resynthesis; Jasin and Rothstein detail how using an intact copy of the sequence makes this route largely error-free. Branzei and Foiani explain why the choice is coupled to the cell cycle: homologous recombination is favoured in S and G2 phases when a sister chromatid is available as a template, while end joining can act when no such template is present.

Clinical relevance

Components of homologous recombination, including BRCA1 and BRCA2, are tumour suppressors whose loss is associated with hereditary cancer predisposition and with sensitivity of tumours to certain DNA-damaging and targeted agents; this entry describes these associations as mechanistic background and not as guidance for the diagnosis or treatment of any individual.

History

Homologous recombination was first understood through genetic studies of meiosis and microbial recombination, and its role in repairing chromosomal double-strand breaks was established in yeast and then in mammalian cells. The molecular components of non-homologous end joining were defined partly through radiation-sensitive and immunodeficient mutants, since the pathway also joins the breaks generated during antibody gene rearrangement, and the two pathways were later placed within the broader DNA damage response.

Key figures

• Maria Jasin
• Rodney Rothstein
• Michael Lieber
• Stephen Jackson

Seminal works

• jasin-rothstein-2013
• lieber-2010
• branzei-foiani-2008

Frequently asked questions

Why is homologous recombination considered more accurate than end joining?

Homologous recombination copies the missing sequence from an intact homologous template, usually the sister chromatid, so the original sequence is restored, whereas non-homologous end joining rejoins the ends directly and may add or remove a few nucleotides at the junction.

When does the cell use each pathway?

Homologous recombination is favoured in S and G2 phases when a sister chromatid is available as a template, while non-homologous end joining can operate throughout the cell cycle, including when no template is present.