Homologous recombination pathway

Fig. 1. Proteins in DNA repair pathways. DNA repair proteins are listed for each of the following pathways BER (Base Excision Repair), NER (Nucleotide Excision Repair), MMR (Mismatch Repair), HR (Homologous Recombination), and NHEJ (Nonhomologous End Joining). PARP1/2 and BRCA1/2 are relevant in BER and HR pathways, respectively.

DNA repair pathways can be divided into those that respond to SSB and those that respond to DSB. SSB repair pathways include base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER). DSB repair pathways include nonhomologous end joining (NHEJ) and homologous recombination (HR). The proteins involved in these DNA repair pathways are shown in Fig. 1. 

A likely pathway for homologous recombination during meiosis is outlined in Figure 25-31a. The model has four key features. First, homologous chromosomes are aligned. Second, a double-strand break in a DNA mole-... 

In this double-strand break repair model for recombination, the 3 ends are used to initiate the genetic exchange. Once paired with the complementary strand on the intact homolog, a region of hybrid DNA is created that contains complementary strands from two different parent DNAs (the product of step (2)in Fig. 25-31a). Each of the 3 ends can then act as a primer for DNA replication. The structures thus formed, Holliday intermediates (Fig. 25 31b), are a feature of homologous genetic recombination pathways in all organisms. 

The repair of stalled replication forks entails a coordinated transition from replication to recombination and back to replication. The recombination steps function to fill the DNA gap or rejoin the broken DNA branch to recreate the branched DNA structure at the replication fork. Lesions left behind in what is now duplex DNA are repaired by pathways such as base-excision or nucleotide-excision repair. Thus a wide range of enzymes encompassing every aspect of DNA metabolism ultimately take part in the repair of a stalled replication fork. This type of repair process is clearly a primary function of the homologous recombination system of every cell, and defects in recombinational DNA repair play an important role in human disease (Box 25-1). 

Smith, G. R., Homologous recombination in E. coli Multiple pathways for multiple reasons. Cell 58 807-809, 1989. 

Eukaryotic cells possess two pathways for the repair of DSBs. One pathway is homologous recombination and appears to be very similar to the one described above in E. coli. However, much less is known about the details of this pathway in mammalian cells. In yeast, homologous recombination is the major pathway for the repair of DSBs. In mammalian cells it is restricted to the late S and G2 phases of the cell cycle. The second pathway is called nonhomologous end joining (NHEJ), and it is thought to be the major pathway for the repair of DSBs in mammalian cells. The two pathways differ in the proteins that participate in them, and they also significantly differ in the outcomes they produce. Homologous recombination produces few errors, whereas NHEJ is error-prone. 

The homologous recombination repair pathway is highly complex, in part perhaps as a consequence of the diverse collection of structures on which it acts. Many proteins have been implicated in this pathway, but their real specific roles in the... 

Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi H, Yamaguchi-Iwai Y, Shinohara A, Takeda S. Homologous recombination and non-homologous end-joining pathways of DNA double-strand break repair have overlapping roles in the maintenance of chromosomal integrity in vertebrate cells. EMBO J. 1998 17 5497-5508. 

In many recombination pathways, a DNA molecule with a free end recombines with a DNA molecule having no free ends available for interaction. DNA molecules with free ends are the common result of double-stranded DNA breaks, but they may also be generated in DMA replication if the replication complex stalls. This type of recombination has been studied extensively in E. coli, but it also takes place in other organisms through the action of proteins homologous to those of E. a)[i. Often dozens of proteins participate in the complete recombination process. However, the key protein is RecA, another member of the AAA... 

Fanconi s anaemia (FA) is an autosomal disorder with bone marrow failure, variable presence of developmental abnormalities, hypersensitivity to DNA cross-linking agents, and a very high incidence of cancer. Different complementation groups have been cloned, but the exact pathway remains uncertain. However, data suggest that the syndrome is linked to mutations in XRCC9 and XRCCl 1 and therefore to defects in the homologous recombination repair pathway (summarized in [26]). 

Helleday, T. (2003). Pathways for mitotic homologous recombination in mammalian cells. Mutat Res 532, 103-115. 

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