Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders

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dc.contributor.authorLokanga, Rachel Adiheen_ZA
dc.contributor.authorSenejani, Alireza Ghodsien_ZA
dc.contributor.authorSweasy, Joann Balazsen_ZA
dc.contributor.authorUsdin, Karenen_ZA
dc.date.accessioned2015-11-18T07:08:40Z
dc.date.available2015-11-18T07:08:40Z
dc.date.issued2015en_ZA
dc.description.abstractAuthor Summary Unstable microsatellites are responsible for a number of debilitating human diseases known as the Repeat Expansion Diseases. The unstable microsatellites, which consist of tandem arrays of short repeat units, are prone to increase in length (expand) on intergenerational transmission and during the lifetime of the individual. Unlike the typical microsatellite instability seen in disorders like Lynch syndrome that arise from mutations in mismatch repair (MMR) genes, expansions of these microsatellites are abolished when MMR is lost. However, how MMR, which normally protects the genome against microsatellite instability, actually promotes microsatellite expansions in these diseases is unknown. There is evidence to suggest that a second DNA repair process, base excision repair (BER), may be involved, but whether the nicks generated early in the BER-process are subverted by an MMR-dependent pathway that generates expansions or whether some MMR proteins contribute to a BER-based expansion process is unclear. Here we show that a mutation that reduces the activity of Polβ, an essential BER enzyme, also reduces the expansion frequency. Since Polβ is essential for key events in BER downstream of the generation of nicks, our data favor a model in which expansions occur via a BER-dependent pathway in which MMR participates.en_ZA
dc.identifier.apacitationLokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015). Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders. <i>PLOS Genetics</i>, http://hdl.handle.net/11427/15132en_ZA
dc.identifier.chicagocitationLokanga, Rachel Adihe, Alireza Ghodsi Senejani, Joann Balazs Sweasy, and Karen Usdin "Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders." <i>PLOS Genetics</i> (2015) http://hdl.handle.net/11427/15132en_ZA
dc.identifier.citationLokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015). Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders. PLoS genetics, 11(4), e1005181-e1005181. doi:10.1371/journal.pgen.1005181en_ZA
dc.identifier.ris TY - Journal Article AU - Lokanga, Rachel Adihe AU - Senejani, Alireza Ghodsi AU - Sweasy, Joann Balazs AU - Usdin, Karen AB - Author Summary Unstable microsatellites are responsible for a number of debilitating human diseases known as the Repeat Expansion Diseases. The unstable microsatellites, which consist of tandem arrays of short repeat units, are prone to increase in length (expand) on intergenerational transmission and during the lifetime of the individual. Unlike the typical microsatellite instability seen in disorders like Lynch syndrome that arise from mutations in mismatch repair (MMR) genes, expansions of these microsatellites are abolished when MMR is lost. However, how MMR, which normally protects the genome against microsatellite instability, actually promotes microsatellite expansions in these diseases is unknown. There is evidence to suggest that a second DNA repair process, base excision repair (BER), may be involved, but whether the nicks generated early in the BER-process are subverted by an MMR-dependent pathway that generates expansions or whether some MMR proteins contribute to a BER-based expansion process is unclear. Here we show that a mutation that reduces the activity of Polβ, an essential BER enzyme, also reduces the expansion frequency. Since Polβ is essential for key events in BER downstream of the generation of nicks, our data favor a model in which expansions occur via a BER-dependent pathway in which MMR participates. DA - 2015 DB - OpenUCT DO - 10.1371/journal.pgen.1005181 DP - University of Cape Town J1 - PLOS Genetics LK - https://open.uct.ac.za PB - University of Cape Town PY - 2015 T1 - Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders TI - Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders UR - http://hdl.handle.net/11427/15132 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/15132
dc.identifier.urihttp://dx.doi.org/10.1371/journal.pgen.1005181
dc.identifier.vancouvercitationLokanga RA, Senejani AG, Sweasy JB, Usdin K. Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders. PLOS Genetics. 2015; http://hdl.handle.net/11427/15132.en_ZA
dc.language.isoengen_ZA
dc.publisherPublic Library of Scienceen_ZA
dc.publisher.departmentDepartment of Molecular and Cell Biologyen_ZA
dc.publisher.facultyFaculty of Scienceen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_ZA
dc.rights.holder© 2015 Lokanga et alen_ZA
dc.rights.urihttp://creativecommons.org/licenses/by/4.0en_ZA
dc.sourcePLOS Geneticsen_ZA
dc.source.urihttp://journals.plos.org/plosgeneticsen_ZA
dc.subject.otherMouse modelsen_ZA
dc.subject.otherPolymerase chain reactionen_ZA
dc.subject.otherSpermen_ZA
dc.subject.otherHeterozygosityen_ZA
dc.subject.otherMutationen_ZA
dc.subject.otherAllelesen_ZA
dc.subject.otherLigasesen_ZA
dc.subject.otherMammalian genomicsen_ZA
dc.titleHeterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disordersen_ZA
dc.typeJournal Articleen_ZA
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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