Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome.
A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and auti...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-08-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002247&type=printable |
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| author | Emily Outwin Gillian Carpenter Weimin Bi Marjorie A Withers James R Lupski Mark O'Driscoll |
| author_facet | Emily Outwin Gillian Carpenter Weimin Bi Marjorie A Withers James R Lupski Mark O'Driscoll |
| author_sort | Emily Outwin |
| collection | DOAJ |
| description | A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression. |
| format | Article |
| id | doaj-art-edf5e486d72649e8982bfd132cad5915 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2011-08-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-edf5e486d72649e8982bfd132cad59152025-08-20T02:05:36ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-08-0178e100224710.1371/journal.pgen.1002247Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome.Emily OutwinGillian CarpenterWeimin BiMarjorie A WithersJames R LupskiMark O'DriscollA novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002247&type=printable |
| spellingShingle | Emily Outwin Gillian Carpenter Weimin Bi Marjorie A Withers James R Lupski Mark O'Driscoll Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. PLoS Genetics |
| title | Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. |
| title_full | Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. |
| title_fullStr | Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. |
| title_full_unstemmed | Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. |
| title_short | Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome. |
| title_sort | increased rpa1 gene dosage affects genomic stability potentially contributing to 17p13 3 duplication syndrome |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1002247&type=printable |
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