Regulation of DNA Pairing in Homologous Recombination

Daley, James M.; Gaines, William A.; Kwon, Youngho; Sung, Patrick

doi:10.1101/cshperspect.a017954

Cited by 86 publications

(79 citation statements)

References 123 publications

(143 reference statements)

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“…This process is followed by precisely coordinated DNA transactions, which are orchestrated by highly conserved homologs/ orthologs of the prototypical RecA/RAD51 DNA homologous pairing and strand exchange proteins (recombinase) (see Li and Heyer 2008;Zelensky et al 2014;Morrical 2015). In S. cerevisae, and with the help of recombination mediators, the ScRad51 and/or the RecA/RAD51 paralog ScDmc1 form a nucleoprotein filament (NPF) on the 3 0 -ssDNA overhangs (Sung 1997;New et al 1998;Shinohara and Ogawa 1998;Gasior et al 2001;Liu et al 2010Liu et al , 2011Carreira and Kowalczykowski 2011;Kojic et al 2011;Murayama et al 2013;Sasanuma et al 2013;Daley et al 2014). One of the RecA/RAD51 NPFs assembled on the 3 0 -ressected ends of the DSB then catalyzes the invasion of a homologous parental double-stranded DNA (dsDNA; donor template) forming a displacement loop (D-loop).…”

Section: Homologous Recombinationmentioning

confidence: 99%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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Homologous recombination (HR) and mismatch repair (MMR) are inextricably linked. HR pairs homologous chromosomes before meiosis I and is ultimately responsible for generating genetic diversity during sexual reproduction. HR is initiated in meiosis by numerous programmed DNA double-strand breaks (DSBs; several hundred in mammals). A characteristic feature of HR is the exchange of DNA strands, which results in the formation of heteroduplex DNA. Mismatched nucleotides arise in heteroduplex DNA because the participating parental chromosomes contain nonidentical sequences. These mismatched nucleotides may be processed by MMR, resulting in nonreciprocal exchange of genetic information (gene conversion). MMR and HR also play prominent roles in mitotic cells during genome duplication; MMR rectifies polymerase misincorporation errors, whereas HR contributes to replication fork maintenance, as well as the repair of spontaneous DSBs and genotoxic lesions that affect both DNA strands. MMR suppresses HR when the heteroduplex DNA contains excessive mismatched nucleotides, termed homeologous recombination. The regulation of homeologous recombination by MMR ensures the accuracy of DSB repair and significantly contributes to species barriers during sexual reproduction. This review discusses the history, genetics, biochemistry, biophysics, and the current state of studies on the role of MMR in homologous and homeologous recombination from bacteria to humans.

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Section: Homologous Recombinationmentioning

confidence: 99%

Mismatch Repair during Homologous and Homeologous Recombination

Spies

Fishel

2015

Cold Spring Harb Perspect Biol

148

150

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“…Inactive HR causes loss of faithful DNA repair and leads to genetic instability, whereas excessive HR interferes with cellular processes such as replication, transcription, and telomere maintenance and also can lead to gross chromosomal rearrangements (3). In human cells, the assembly of the RAD51 nucleoprotein filament is aided by the recombination mediator BRCA2 and RAD51 paralogs (9,10), antagonized by antirecombinases (11) and the heteroduplex rejection machinery (12), and is also regulated by posttranslational modifications. Activities of RAD51 in the cell are influenced by three types of phosphorylation.…”

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confidence: 99%

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

Subramanyam

Ismail

Bhattacharya

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The DNA strand exchange protein RAD51 facilitates the central step in homologous recombination, a process fundamentally important for accurate repair of damaged chromosomes, restart of collapsed replication forks, and telomere maintenance. The active form of RAD51 is a nucleoprotein filament that assembles on single-stranded DNA (ssDNA) at the sites of DNA damage. The c-Abl tyrosine kinase and its oncogenic counterpart BCR-ABL fusion kinase phosphorylate human RAD51 on tyrosine residues 54 and 315. We combined biochemical reconstitutions of the DNA strand exchange reactions with total internal reflection fluorescence microscopy to determine how the two phosphorylation events affect the biochemical activities of human RAD51 and properties of the RAD51 nucleoprotein filament. By mimicking RAD51 tyrosine phosphorylation with a nonnatural amino acid, p-carboxymethyl-L-phenylalanine (pCMF), we demonstrated that Y54 phosphorylation enhances the RAD51 recombinase activity by at least two different mechanisms, modifies the RAD51 nucleoprotein filament formation, and allows RAD51 to compete efficiently with ssDNA binding protein RPA. In contrast, Y315 phosphorylation has little effect on the RAD51 activities. Based on our work and previous cellular studies, we propose a mechanism underlying RAD51 activation by c-Abl/BCR-ABL kinases.RAD51 recombinase | c-Abl tyrosine kinase | homologous recombination | single-molecule total internal reflection fluorescence microscopy | phosphorylation T he DNA in the human genome is constantly subjected to damage. This damage is a byproduct of normal cellular metabolism, exposure to radiation, and environmental mutagens (1). Homologous recombination (HR) and the pathways that use the machinery of HR are responsible for the accurate repair of the most deleterious DNA lesions, including double-stranded DNA breaks (DSBs), interstrand DNA cross-links, and damaged replication forks, and thereby contribute to maintenance of the stable genome (2-5). HR also plays an important role in telomere maintenance (6). HR, a process highly conserved throughout evolution, is carried out through a precisely coordinated and tightly regulated series of events. The key step in HR is the assembly of a RecA-family recombinase (phage UvsX, bacterial RecA, archaeal RadA, or eukaryotic RAD51) onto resected single-stranded DNA (ssDNA). The recombinase forms a nucleoprotein filament that then invades homologous duplex DNA, resulting in a displacement loop structure that can be used as a primer for synthesis using the intact duplex as a template. Similar to its bacterial and yeast homologs, the human RAD51 binds ssDNA in an ATP-dependent manner (7). The nucleoprotein filament formed by the ATP-bound RAD51 is arranged such that each RAD51 monomer binds three nucleotides, forming the pairing unit in these reactions (8). Beyond these basic attributes, the characteristics of human RAD51 protein differ significantly from its archaeal, bacterial, and yeast homologs.The critical role of HR requires all steps of this process ...

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“…Like dHJ, the SDSA process begins with a pairing reaction between one of the resected ends of a DSB and the homologous duplex region of the sister chromatid. The heteroduplex/D-loop structure generated in SDSA is more dynamic than the one formed in dHJ; however, DNA synthesis extends the heteroduplex in the 3 0 direction, but the heteroduplex is rapidly resolved by branch migration of the trailing edge of the D-loop (see Daley et al 2014). The result is a Dloop that translocates along the sister duplex, and an extended invading strand that is only transiently associated with its template (Fig.…”

Section: Synthesis-dependent Strand Annealingmentioning

confidence: 99%

“…3). Evidence suggests that in yeast cells, the DNA helicases Sgs1 and Srs2 promote the formation of NCOs via SDSA, and also suppress COs by dismantling Holliday junctioncontaining intermediates (Ira et al 2003;Miura et al 2012;Daley et al 2013Daley et al , 2014Mitchel et al 2013). Sgs1 promotes the dissolution of dHJ structures in collaboration with Top3 and Rmi1 (Cejka et al 2010;Hickson and Mankouri 2011;Mankouri et al 2011).…”

Section: Dna Pairing and Annealingmentioning

confidence: 99%

“…On the other hand, ATP hydrolysis appears to regulate filament activity and to provide for filament turnover or dynamic instability (Kowalczykowski 1991;Cox 2003;Liu et al 2006Liu et al , 2011a. In addition, DNA-pairing protein-promoted pairing reactions are stimulated by ssDNA-binding and recombination mediator proteins, which are described below (see Daley et al 2014;Zelensky et al 2014). …”

Section: Properties Of Dna-pairing Proteinsmentioning

confidence: 99%

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DNA-Pairing and Annealing Processes in Homologous Recombination and Homology-Directed Repair

Morrical

2015

Cold Spring Harb Perspect Biol

116

127

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The formation of heteroduplex DNA is a central step in the exchange of DNA sequences via homologous recombination, and in the accurate repair of broken chromosomes via homology-directed repair pathways. In cells, heteroduplex DNA largely arises through the activities of recombination proteins that promote DNA-pairing and annealing reactions. Classes of proteins involved in pairing and annealing include RecA-family DNA-pairing proteins, single-stranded DNA (ssDNA)-binding proteins, recombination mediator proteins, annealing proteins, and nucleases. This review explores the properties of these pairing and annealing proteins, and highlights their roles in complex recombination processes including the double Holliday junction (DhJ) formation, synthesis-dependent strand annealing, and singlestrand annealing pathways-DNA transactions that are critical both for genome stability in individual organisms and for the evolution of species.

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Regulation of DNA Pairing in Homologous Recombination

Cited by 86 publications

References 123 publications

Mismatch Repair during Homologous and Homeologous Recombination

Mismatch Repair during Homologous and Homeologous Recombination

Tyrosine phosphorylation stimulates activity of human RAD51 recombinase through altered nucleoprotein filament dynamics

DNA-Pairing and Annealing Processes in Homologous Recombination and Homology-Directed Repair

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