Cargando…
RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health
Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in IC...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459755/ https://www.ncbi.nlm.nih.gov/pubmed/28575657 http://dx.doi.org/10.1016/j.molcel.2017.04.021 |
_version_ | 1783242019633627136 |
---|---|
author | Feeney, Laura Muñoz, Ivan M. Lachaud, Christophe Toth, Rachel Appleton, Paul L. Schindler, Detlev Rouse, John |
author_facet | Feeney, Laura Muñoz, Ivan M. Lachaud, Christophe Toth, Rachel Appleton, Paul L. Schindler, Detlev Rouse, John |
author_sort | Feeney, Laura |
collection | PubMed |
description | Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health. |
format | Online Article Text |
id | pubmed-5459755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54597552017-06-14 RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health Feeney, Laura Muñoz, Ivan M. Lachaud, Christophe Toth, Rachel Appleton, Paul L. Schindler, Detlev Rouse, John Mol Cell Article Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health. Cell Press 2017-06-01 /pmc/articles/PMC5459755/ /pubmed/28575657 http://dx.doi.org/10.1016/j.molcel.2017.04.021 Text en © 2017 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Feeney, Laura Muñoz, Ivan M. Lachaud, Christophe Toth, Rachel Appleton, Paul L. Schindler, Detlev Rouse, John RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title | RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title_full | RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title_fullStr | RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title_full_unstemmed | RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title_short | RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health |
title_sort | rpa-mediated recruitment of the e3 ligase rfwd3 is vital for interstrand crosslink repair and human health |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459755/ https://www.ncbi.nlm.nih.gov/pubmed/28575657 http://dx.doi.org/10.1016/j.molcel.2017.04.021 |
work_keys_str_mv | AT feeneylaura rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT munozivanm rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT lachaudchristophe rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT tothrachel rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT appletonpaull rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT schindlerdetlev rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth AT rousejohn rpamediatedrecruitmentofthee3ligaserfwd3isvitalforinterstrandcrosslinkrepairandhumanhealth |