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

 

Show simple item record

dc.contributor.author Lokanga, Rachel Adihe en_ZA
dc.contributor.author Senejani, Alireza Ghodsi en_ZA
dc.contributor.author Sweasy, Joann Balazs en_ZA
dc.contributor.author Usdin, Karen en_ZA
dc.date.accessioned 2015-11-18T07:08:40Z
dc.date.available 2015-11-18T07:08:40Z
dc.date.issued 2015 en_ZA
dc.identifier.citation Lokanga, 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.1005181 en_ZA
dc.identifier.uri http://hdl.handle.net/11427/15132
dc.identifier.uri http://dx.doi.org/10.1371/journal.pgen.1005181
dc.description.abstract 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. en_ZA
dc.language.iso eng en_ZA
dc.publisher Public Library of Science en_ZA
dc.rights This 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.uri http://creativecommons.org/licenses/by/4.0 en_ZA
dc.source PLOS Genetics en_ZA
dc.source.uri http://journals.plos.org/plosgenetics en_ZA
dc.subject.other Mouse models en_ZA
dc.subject.other Polymerase chain reaction en_ZA
dc.subject.other Sperm en_ZA
dc.subject.other Heterozygosity en_ZA
dc.subject.other Mutation en_ZA
dc.subject.other Alleles en_ZA
dc.subject.other Ligases en_ZA
dc.subject.other Mammalian genomics en_ZA
dc.title Heterozygosity for a hypomorphic polβ mutation reduces the expansion frequency in a mouse model of the fragile x-related disorders en_ZA
dc.type Journal Article en_ZA
dc.rights.holder © 2015 Lokanga et al en_ZA
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Science en_ZA
dc.publisher.department Department of Molecular and Cell Biology en_ZA
uct.type.filetype Text
uct.type.filetype Image
dc.identifier.apacitation Lokanga, 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/11427/15132 en_ZA
dc.identifier.chicagocitation Lokanga, 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/11427/15132 en_ZA
dc.identifier.vancouvercitation Lokanga 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.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


Files in this item

This item appears in the following Collection(s)

Show simple item record

This 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. Except where otherwise noted, this item's license is described as This 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.