De novo prediction of DNA-binding specificities for Cys2His2 zinc finger proteins

Persikov, Anton V.; Singh, Mona

doi:10.1093/nar/gkt890

Cited by 195 publications

(227 citation statements)

References 60 publications

(74 reference statements)

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“…These included the alleles for the mice used in our study. We generated a PWM of the putative binding site for each of these 74 alleles using the polynomial SVM and the method of Persikov et al (2009) and Persikov and Singh (2014) and then compared each motif to the set of all 74 binding sites using STAMP (Mahony and Benos 2007). We found that all motifs aligned to the binding site for their respective allele of PRDM9 with an E-value <0.005 (Supplemental Table S2).…”

Section: Identification Of Sequence Motifsmentioning

confidence: 99%

The evolutionary turnover of recombination hot spots contributes to speciation in mice

et al. 2016

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Meiotic recombination is required for the segregation of homologous chromosomes and is essential for fertility. In most mammals, the DNA double-strand breaks (DSBs) that initiate meiotic recombination are directed to a subset of genomic loci (hot spots) by sequence-specific binding of the PRDM9 protein. Rapid evolution of the DNA-binding specificity of PRDM9 and gradual erosion of PRDM9-binding sites by gene conversion will alter the recombination landscape over time. To better understand the evolutionary turnover of recombination hot spots and its consequences, we mapped DSB hot spots in four major subspecies of Mus musculus with different Prdm9 alleles and in their F1 hybrids. We found that hot spot erosion governs the preferential usage of some Prdm9 alleles over others in hybrid mice and increases sequence diversity specifically at hot spots that become active in the hybrids. As crossovers are disfavored at such hot spots, we propose that sequence divergence generated by hot spot turnover may create an impediment for recombination in hybrids, potentially leading to reduced fertility and, eventually, speciation.

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Section: Identification Of Sequence Motifsmentioning

confidence: 99%

The evolutionary turnover of recombination hot spots contributes to speciation in mice

et al. 2016

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“…The identities of these amino acids are the principle determinants of the DNA sequence recognized (Supplemental Fig. S2a,b;Gupta et al 2014;Persikov and Singh 2014).…”

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confidence: 99%

Structural basis for human PRDM9 action at recombination hot spots

et al. 2016

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The multidomain zinc finger (ZnF) protein PRDM9 (PRD1-BF1-RIZ1 homologous domain-containing 9) is thought to influence the locations of recombination hot spots during meiosis by sequence-specific DNA binding and trimethylation of histone H3 Lys4. The most common variant of human PRDM9, allele A (hPRDM9 A ), recognizes the consensus sequence 5 ′ -NCCNCCNTNNCCNCN-3 ′ . We cocrystallized ZnF8-12 of hPRDM9 A with an oligonucleotide representing a known hot spot sequence and report the structure here. ZnF12 was not visible, but ZnF8-11, like other ZnF arrays, follows the right-handed twist of the DNA, with the α helices occupying the major groove. Each α helix makes hydrogen-bond (H-bond) contacts with up to four adjacent bases, most of which are purines of the complementary DNA strand. The consensus C:G base pairs H-bond with conserved His or Arg residues in ZnF8, ZnF9, and ZnF11, and the consensus T:A base pair H-bonds with an Asn that replaces His in ZnF10. Most of the variable base pairs (N) also engage in H bonds with the protein. These interactions appear to compensate to some extent for changes from the consensus sequence, implying an adaptability of PRDM9 to sequence variations. We investigated the binding of various alleles of hPRDM9 to different hot spot sequences. Allele C was found to bind a C-specific hot spot with higher affinity than allele A bound A-specific hot spots, perhaps explaining why the former is dominant in A/C heterozygotes. Allele L13 displayed higher affinity for several A-specific sequences, allele L9/L24 displayed lower affinity, and allele L20 displayed an altered sequence preference. These differences can be rationalized structurally and might contribute to the variation observed in the locations and activities of meiotic recombination hot spots.

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“…Most commonly, proceeding leftward in the amino acid sequence toward the N terminus, residues at positions À1, À4, and À7 (or À8) make base-specific contacts through their side chains; the identities of these amino acids are the principle determinants of the DNA sequence recognized (Supplemental Fig. S1A), although by no means the only ones (Gupta et al 2014;Persikov and Singh 2014).…”

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confidence: 99%

Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence

et al. 2014

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In mammalian DNA, cytosine occurs in several chemical forms, including unmodified cytosine (C), 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). 5mC is a major epigenetic signal that acts to regulate gene expression. 5hmC, 5fC, and 5caC are oxidized derivatives that might also act as distinct epigenetic signals. We investigated the response of the zinc finger DNAbinding domains of transcription factors early growth response protein 1 (Egr1) and Wilms tumor protein 1 (WT1) to different forms of modified cytosine within their recognition sequence, 59-GCG(T/G)GGGCG-39. Both displayed high affinity for the sequence when C or 5mC was present and much reduced affinity when 5hmC or 5fC was present, indicating that they differentiate primarily oxidized C from unoxidized C, rather than methylated C from unmethylated C. 5caC affected the two proteins differently, abolishing binding by Egr1 but not by WT1. We ascribe this difference to electrostatic interactions in the binding sites. In Egr1, a negatively charged glutamate conflicts with the negatively charged carboxylate of 5caC, whereas the corresponding glutamine of WT1 interacts with this group favorably. Our analyses shows that zinc finger proteins (and their splice variants) can respond in modulated ways to alternative modifications within their binding sequence.

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De novo prediction of DNA-binding specificities for Cys2His2 zinc finger proteins

Cited by 195 publications

References 60 publications

The evolutionary turnover of recombination hot spots contributes to speciation in mice

The evolutionary turnover of recombination hot spots contributes to speciation in mice

Structural basis for human PRDM9 action at recombination hot spots

Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence

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