Cargando…
Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair
Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic dele...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641073/ https://www.ncbi.nlm.nih.gov/pubmed/29069730 http://dx.doi.org/10.18632/oncotarget.17776 |
_version_ | 1783271153043767296 |
---|---|
author | Jahid, Sohail Sun, Jian Gelincik, Ozkan Blecua, Pedro Edelmann, Winfried Kucherlapati, Raju Zhou, Kathy Jasin, Maria Gümüş, Zeynep H. Lipkin, Steven M. |
author_facet | Jahid, Sohail Sun, Jian Gelincik, Ozkan Blecua, Pedro Edelmann, Winfried Kucherlapati, Raju Zhou, Kathy Jasin, Maria Gümüş, Zeynep H. Lipkin, Steven M. |
author_sort | Jahid, Sohail |
collection | PubMed |
description | Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1, Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dMMR CRC). Analysis of The Cancer Genome Atlas CRC data revealed that dMMR CRCs have higher genome-wide DR HeR rates than MMR proficient CRCs, and that dMMR CRCs have deletion hotspots in tumor suppressors FHIT/WWOX at chromosomal fragile sites FRA3B and FRA16D (which have elevated DSB rates) flanked by paired homologous DRs and inverted repeats (IR). Overall, these data provide novel insights into the MMR-dependent HeR inhibition mechanism and its role in tumor suppression. |
format | Online Article Text |
id | pubmed-5641073 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56410732017-10-24 Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair Jahid, Sohail Sun, Jian Gelincik, Ozkan Blecua, Pedro Edelmann, Winfried Kucherlapati, Raju Zhou, Kathy Jasin, Maria Gümüş, Zeynep H. Lipkin, Steven M. Oncotarget Research Paper Homologous recombination (HR) enables precise DNA repair after DNA double strand breaks (DSBs) using identical sequence templates, whereas homeologous recombination (HeR) uses only partially homologous sequences. Homeologous recombination introduces mutations through gene conversion and genomic deletions through single-strand annealing (SSA). DNA mismatch repair (MMR) inhibits HeR, but the roles of mammalian MMR MutL homologues (MLH1, PMS2 and MLH3) proteins in HeR suppression are poorly characterized. Here, we demonstrate that mouse embryonic fibroblasts (MEFs) carrying Mlh1, Pms2, and Mlh3 mutations have higher HeR rates, by using 7,863 uniquely mapping paired direct repeat sequences (DRs) in the mouse genome as endogenous gene conversion and SSA reporters. Additionally, when DSBs are induced by gamma-radiation, Mlh1, Pms2 and Mlh3 mutant MEFs have higher DR copy number alterations (CNAs), including DR CNA hotspots previously identified in mouse MMR-deficient colorectal cancer (dMMR CRC). Analysis of The Cancer Genome Atlas CRC data revealed that dMMR CRCs have higher genome-wide DR HeR rates than MMR proficient CRCs, and that dMMR CRCs have deletion hotspots in tumor suppressors FHIT/WWOX at chromosomal fragile sites FRA3B and FRA16D (which have elevated DSB rates) flanked by paired homologous DRs and inverted repeats (IR). Overall, these data provide novel insights into the MMR-dependent HeR inhibition mechanism and its role in tumor suppression. Impact Journals LLC 2017-05-10 /pmc/articles/PMC5641073/ /pubmed/29069730 http://dx.doi.org/10.18632/oncotarget.17776 Text en Copyright: © 2017 Jahid et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Research Paper Jahid, Sohail Sun, Jian Gelincik, Ozkan Blecua, Pedro Edelmann, Winfried Kucherlapati, Raju Zhou, Kathy Jasin, Maria Gümüş, Zeynep H. Lipkin, Steven M. Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title | Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title_full | Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title_fullStr | Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title_full_unstemmed | Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title_short | Inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor FHIT and WWOX deletions by DNA mismatch repair |
title_sort | inhibition of colorectal cancer genomic copy number alterations and chromosomal fragile site tumor suppressor fhit and wwox deletions by dna mismatch repair |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641073/ https://www.ncbi.nlm.nih.gov/pubmed/29069730 http://dx.doi.org/10.18632/oncotarget.17776 |
work_keys_str_mv | AT jahidsohail inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT sunjian inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT gelincikozkan inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT blecuapedro inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT edelmannwinfried inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT kucherlapatiraju inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT zhoukathy inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT jasinmaria inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT gumuszeyneph inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair AT lipkinstevenm inhibitionofcolorectalcancergenomiccopynumberalterationsandchromosomalfragilesitetumorsuppressorfhitandwwoxdeletionsbydnamismatchrepair |