Eukaryotic Recombination: Initiation by Double‐Strand Breaks

Abstract

A double‐strand break (DSB) in one deoxyribonucleic acid (DNA) double helix, caused by DNA damaging agents such as ionising radiation or normal metabolic processes, can stimulate repair through multiple pathways. Homologous recombination (HR) utilises a second unbroken DNA double helix containing homologous sequences as a donor of genetic information to restore the intact DNA structure, while nonhomologous end joining (NHEJ) relegates broken DNA ends together with little to no homology. Deficiency in these repair pathways can cause genome instability can drive carcinogenesis. DSB stimulated repair can cause illegitimate HR between heterologous chromosome of the ligation of ends of DNA from heterologous chromosomes.

  • Exogenous and endogenous agents can cause deoxyribonucleic acid (DNA) breaks leading to genome instability.
  • Repair of double‐strand breaks (DSB) in eukaryotes occurs by either homology‐dependent or homology‐independent mechanisms.
  • Homologous recombination (HR) facilitates high‐fidelity repair of DSBs and other plausible DNA damage.
  • Site‐specific DSBs within the genome are used to study the explicit mechanism involved in the DSB repair.
  • Unlike other model organisms, HR in higher eukaryotes requires additional protein factors.
  • Mutations in HR proteins can increase predisposition to cancer.

Keywords: DNA repair; double‐strand break; genome stability; recombination; end joining

Figure 1. Two models for DSB‐induced recombination. Following a double‐strand break in one DNA helix, a processed end can invade a homologous template to initiate repair. This process may either proceed by a replication‐based mechanism that results in gene conversion products, or by the classical double‐strand repair model that can result in both crossover and noncrossover products, depending on resolution of the Holliday junction intermediate.
Figure 2. Model for single strand annealing. Following a DSB between homologous sequences such as repetitive elements, both ends are processed by exonucleolytic digestion to generate 3′ single strand tails. Homologous sequences base pair and extruded ends cleaved away.
Figure 3. Model for mating type switching in yeast. Following a double‐strand break at one locus by the HO endonuclease, invasion of a single‐strand tail from the broken MAT locus into the unbroken donor leads to a replication‐based recombination event in which gene conversion leads to mating‐type switching.
Figure 4. Model for CRISP/Cas9 system. Following a Cas9 induced DSB at a chosen sequence homologous to the gRNA, repair produces mutation or HR if a homologous template is also provided in the system.
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Lalwani, Kiran, Goodenow, Donna, and Richardson, Christine(Aug 2020) Eukaryotic Recombination: Initiation by Double‐Strand Breaks. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029148]