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Recombination DNA repair

Recombination DNA Repair definition

Recombination DNA Repair definition: A reparative process in response to DNA damage, such as caused by UV light

Recombination DNA Repair Definition

Recombination DNA repair is a biological reparative process in response to DNA damage caused by exogenous agents (e.g. UV light). The process is done by generating functional DNA by breaking and rejoining DNA strands and repairing based on homologous unaltered DNA strand.

DNA structure overview

DNA (deoxyribonucleic acid) is a nucleic acid consisting of monomeric nucleotides. Each nucleotide is made up of phosphoric acid, sugar, and nitrogenous base. Another nucleic acid is RNA (ribonucleic acid). DNA differs from RNA in having a double helical configuration as opposed to RNA, which is single-stranded. They also differ in the nucleotide components. DNA has a deoxyribose sugar backbone whereas RNA has ribose. For further comparison between DNA and RNA, read here. The bases present in DNA are adenine, guanine, cytosine, and thymine. Adenine complementary base pairs with thymine whereas guanine, with cytosine. Prior to mitosis and meiosis, DNA is replicated. It is also during this time that DNA is susceptible to damage, such as exposure to UV light.

DNA damage

As mentioned, one of the ways by which DNA is damaged is by exposure to UV. UV light creates nicks on the DNA molecule, splitting the latter into two fragments. As a result, some nucleotides near the nicks may be lost.

The body, though, has reparative mechanisms to correct mutations and errors. The two major systems for repair are nucleotide excision repair and recombinational DNA repair. (Ref.1)

Repair process

The cell has repair mechanisms to correct DNA damage. For instance, a cell that is exposed to high-energy radiation could cause the chromosome to break into two pieces. The cell repairs a broken chromosome by non-homologous end joining or by homologous recombination.

Nonhomologous end joining vs homologous recombination

The problem with double-stranded breaks (DSBs) is the plausibility of losing a large portion of the chromosome at the breaking point. To repair by a non-homologous repair mechanism, the broken ends of the chromosomes are joined back together. Since a portion of the chromosome might have been lost following breakage, the mere end-joining of two chromosomal segments at the breaking site could likely lead to mutation due to lost nucleotides. This is somehow averted when the repair strategy is by the more-complex homologous recombination.

In the homologous recombination repair process, the nucleotide sequence from the other pair of homologous chromosomes (called “homologue”) is an example of the template used to create the lost portion of the damaged chromosome. Homologous chromosomes are paired chromosomes in the nucleus. Chromosomes that have the same gene loci, gene sequence, centromere location, and chromosomal length but may have different alleles are referred to as homologous. Humans, in particular, have 23 pairs of chromosomes (22 of them are homologous autosomal). Half of them are paternal whereas the other half, maternal. These chromosomes pair up during meiosis but not during mitosis.

Pre-synapstic events

Detection and signaling. In eukaryotic cells, MRN complex (Mre11-Rad50-Nbs1 complex) was identified to play a crucial role. (Ref. 2) In fact, it is also the initiator of the non-homologous end joining pathway. It detects the presence of double-strand breaks by binding to the free ends of the DNA fragments. In the figure below, it shows the schematic diagram where MRN complexes are bound to DNA termini. In the actual process, multiple MRN complexes cluster at the termini but in this figure, only one is shown for simplicity.

MRN complex
MRN complex molecules bound to the two chromosomal fragments, detecting the double-stranded breaks. Source: Lamarche, B. J., Orazio, N. I., & Weitzman, M. D. (2010). The MRN complex in double-strand break repair and telomere maintenance. FEBS Letters, 584(17), 3682–3695. https://doi.org/10.1016/j.febslet.2010.07.029

‌After binding, it then calls for DNA damage protein kinases on the site to launch cascades of signal transduction pathways for DNA damage response. (Ref. 2) The primary signaling kinases include ATM ser/thr kinase (ataxia-telangiectasia mutation serine/threonine kinase), ATR (ATM and Rad3-related kinase), and DNA-PK (DNA- dependent protein kinase).  ATM naturally occurs as a homodimer. It binds to another ATM monomer to form a dimer when there is DNA damage. The dimer is recruited at the breakage site. This causes the MRN complex to alter its configuration to enable its NBS1 subunit to interact with the ATM dimer.

The activation of ATM and ATR leads to a network of signaling pathways. In human cells, the kinase pathways lead to the phosphorylation of more than 700 proteins, including checkpoint kinases (Chk1 and Chk2) that promote arrests in the cell cycle, those that promote chromatin remodeling, and those responsible for lesion repair. (Ref. 2)

DSB end resection. The Mre-11 subunit of the MRN complex has a catalytic function in resection. It has both 5’-flap endonuclease activity and 3’–> 5’ exonuclease activity. Its endonuclease activity is what promotes resection by internal cleavage of the 5’ strand. (Ref. 3) The MRN complexes move to the opposite directions, away from the DSB ends, and make an endonuclease cut. The 3’ to 5’ endonuclease activity leads to the cutting of the nucleotides near the ends, creating 3’ overhangs on both chromosomal fragments.

The end resection needs proteins such as CtIP. CtIP (carboxy-terminal binding protein-interacting protein) has a role in the activation of the G2/M checkpoint that blocks the progression of the cell cycle to the M phase. (Ref. 4) CtIP is also believed to have a role in DSB end resection. (Ref. 4) Ctlp proteins are recruited at the breakage site specifically at S/G2 cell cycle, when sister chromatids can act as a template. These proteins may interact with the MRN complexes that are bound to the DNA following phosphorylation by cyclin-dependent kinases (CDKs). (Ref. 4)

Nucleoprotein filament formation. The resection of DSB ends results in the formation of an overhang, which is also called single-stranded DNA (ssDNA). Following resection is the recruitment of proteins, such as RPA, BRCA1, BRCA2, Rad51, Rad52, and Rad54. (Ref. 5) RPA or replication protein A binds to the ssDNA to prevent the latter from winding back on itself. It is eventually replaced by Rad51. Rad51 is a key recombinase protein that catalyzes the search for a homologous and exchange with a homologous sequence. (Ref. 5) Multiple subunits of Rad51 bind to ssDNA. The overhang with Rad51 subunits bound to it forms the nucleoprotein filament. (Ref. 6) This initiates recombination events that require intact (undamaged) homologous sequences called donor DNA. (Ref. 7)

Synaptic phase

In mitotic cells, the template used for lesion repair is the sister chromatid. The reparative process occurs during the S and G2 phases. In meiotic cells, the template is a sister chromatid (when in meiosis I) or a homologue (during meiosis II). (Ref. 2)

When the donor DNA is found, the nucleoprotein filament invades the DNA duplex. It, then, leads to the displacement of the homologous DNA strand, forming a D-loop. (Ref. 5) The displaced DNA strand is, then, used as a template as well for DNA synthesis. This phase leads to the generation of DNA portions with a nucleotide sequence that complements the homologous (donor) strand.

Post-synaptic phase

Two Holliday junctions are produced. The resolution of Holliday junctions occurs with or without crossing over. (Ref. 5)

homologous recombinantion phases

See also


    1. RECOMBINATIONAL DNA REPAIR. (2011). Photobiology.Info. http://photobiology.info/recRepair.htmlLamarche, B. J., Orazio, N. I., & Weitzman, M. D. (2010). The MRN complex in double-strand break repair and telomere maintenance. FEBS Letters, 584(17), 3682–3695. https://doi.org/10.1016/j.febslet.2010.07.029
    2. Lamarche, B. J., Orazio, N. I., & Weitzman, M. D. (2010). The MRN complex in double-strand break repair and telomere maintenance. FEBS Letters, 584(17), 3682–3695. https://doi.org/10.1016/j.febslet.2010.07.029
    3. Chen, Y., Liu, H., Zhang, H., Sun, C., Hu, Z., Tian, Q., Peng, C., Jiang, P., Hua, H., Li, X., & Pei, H. (2016). And-1 coordinates with CtIP for efficient homologous recombination and DNA damage checkpoint maintenance. Nucleic Acids Research, 45(5), 2516–2530. https://doi.org/10.1093/nar/gkw1212
    4. You, Z., & Bailis, J. M. (2010). DNA damage and decisions: CtIP coordinates DNA repair and cell cycle checkpoints. Trends in Cell Biology, 20(7), 402–409. https://doi.org/10.1016/j.tcb.2010.04.002
    5. Renodon-Cornire, A., Weigel, P., Le, M., & Fleury, F. (2013). New Potential Therapeutic Approaches by Targeting Rad51- Dependent Homologous Recombination. New Research Directions in DNA Repair. https://doi.org/10.5772/53973
    6. Jasin, M., & Rothstein, R. (2013). Repair of Strand Breaks by Homologous Recombination. Cold Spring Harbor Perspectives in Biology, 5(11), a012740–a012740. https://doi.org/10.1101/cshperspect.a012740
    7. Andriuskevicius, T., Kotenko, O., & Makovets, S. (2018). Putting together and taking apart: assembly and disassembly of the Rad51 nucleoprotein filament in DNA repair and genome stability. Cell Stress, 2(5), 96–112. https://doi.org/10.15698/cst2018.05.134

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