Structural basis for human PRDM9 action at recombination hot spots

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 (hPR...

ver descrição completa

Na minha lista:
Detalhes bibliográficos
Publicado no:Genes Dev
Main Authors: Patel, Anamika, Horton, John R., Wilson, Geoffrey G., Zhang, Xing, Cheng, Xiaodong
Formato: Artigo
Idioma:Inglês
Publicado em: Cold Spring Harbor Laboratory Press 2016
Assuntos:
Research Paper
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC4743056/
https://ncbi.nlm.nih.gov/pubmed/26833727
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1101/gad.274928.115
Tags: Adicionar Tag
Sem tags, seja o primeiro a adicionar uma tag!
id pubmed-4743056
record_format dspace
spelling pubmed-47430562016-02-17 Structural basis for human PRDM9 action at recombination hot spots Patel, Anamika Horton, John R. Wilson, Geoffrey G. Zhang, Xing Cheng, Xiaodong Genes Dev Research Paper 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. Cold Spring Harbor Laboratory Press 2016-02-01 /pmc/articles/PMC4743056/ /pubmed/26833727 http://dx.doi.org/10.1101/gad.274928.115 Text en © 2016 Patel et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
institution US NLM
collection PubMed Central
language Inglês
format Artigo
topic Research Paper
spellingShingle Research Paper
Patel, Anamika
Horton, John R.
Wilson, Geoffrey G.
Zhang, Xing
Cheng, Xiaodong
Structural basis for human PRDM9 action at recombination hot spots
description 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.
author Patel, Anamika
Horton, John R.
Wilson, Geoffrey G.
Zhang, Xing
Cheng, Xiaodong
author_facet Patel, Anamika
Horton, John R.
Wilson, Geoffrey G.
Zhang, Xing
Cheng, Xiaodong
author_sort Patel, Anamika
title Structural basis for human PRDM9 action at recombination hot spots
title_short Structural basis for human PRDM9 action at recombination hot spots
title_full Structural basis for human PRDM9 action at recombination hot spots
title_fullStr Structural basis for human PRDM9 action at recombination hot spots
title_full_unstemmed Structural basis for human PRDM9 action at recombination hot spots
title_sort structural basis for human prdm9 action at recombination hot spots
publisher Cold Spring Harbor Laboratory Press
container_title Genes Dev
publishDate 2016
url https://ncbi.nlm.nih.gov/pmc/articles/PMC4743056/
https://ncbi.nlm.nih.gov/pubmed/26833727
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1101/gad.274928.115
_version_ 1813620131035611136

Registos relacionados