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HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis
Repair of interstrand crosslinks (ICLs) requires the coordinate action of the intra-S phase checkpoint and the Fanconi Anemia (FA) pathway, which promote ICL incision, translesion synthesis, and homologous recombination (reviewed in (1,2)). Previous studies have implicated the 3′-5′ superfamily 2 he...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836231/ https://www.ncbi.nlm.nih.gov/pubmed/24005329 http://dx.doi.org/10.1038/nature12565 |
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author | Adelman, Carrie A. Lolo, Rafal L. Birkbak, Nicolai J. Murina, Olga Matsuzaki, Kenichiro Horejsi, Zuzana Parmar, Kalindi Borel, Valérie Skehel, J. Mark Stamp, Gordon D’Andrea, Alan Sartori, Alessandro A. Swanton, Charles Boulton, Simon J. |
author_facet | Adelman, Carrie A. Lolo, Rafal L. Birkbak, Nicolai J. Murina, Olga Matsuzaki, Kenichiro Horejsi, Zuzana Parmar, Kalindi Borel, Valérie Skehel, J. Mark Stamp, Gordon D’Andrea, Alan Sartori, Alessandro A. Swanton, Charles Boulton, Simon J. |
author_sort | Adelman, Carrie A. |
collection | PubMed |
description | Repair of interstrand crosslinks (ICLs) requires the coordinate action of the intra-S phase checkpoint and the Fanconi Anemia (FA) pathway, which promote ICL incision, translesion synthesis, and homologous recombination (reviewed in (1,2)). Previous studies have implicated the 3′-5′ superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C(3)) and C. elegans (known as Helq-1 or Hel-308(4)). While in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ ssDNA overhangs and also disrupts protein/DNA interactions while translocating along DNA(5,6), little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with HelQ heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralog complex, BCDX2, and functions in parallel to the FA pathway to promote efficient HR at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals. |
format | Online Article Text |
id | pubmed-3836231 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
record_format | MEDLINE/PubMed |
spelling | pubmed-38362312014-04-17 HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis Adelman, Carrie A. Lolo, Rafal L. Birkbak, Nicolai J. Murina, Olga Matsuzaki, Kenichiro Horejsi, Zuzana Parmar, Kalindi Borel, Valérie Skehel, J. Mark Stamp, Gordon D’Andrea, Alan Sartori, Alessandro A. Swanton, Charles Boulton, Simon J. Nature Article Repair of interstrand crosslinks (ICLs) requires the coordinate action of the intra-S phase checkpoint and the Fanconi Anemia (FA) pathway, which promote ICL incision, translesion synthesis, and homologous recombination (reviewed in (1,2)). Previous studies have implicated the 3′-5′ superfamily 2 helicase HELQ/Hel308 in ICL repair in D. melanogaster (known as Mus301 or Spn-C(3)) and C. elegans (known as Helq-1 or Hel-308(4)). While in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3′ ssDNA overhangs and also disrupts protein/DNA interactions while translocating along DNA(5,6), little is known regarding its functions in mammalian organisms. Here we report that HELQ helicase-deficient mice exhibit subfertility, germ cell attrition, ICL sensitivity and tumour predisposition, with HelQ heterozygous mice exhibiting a similar, albeit less severe, phenotype than the null, indicative of haploinsufficiency. We establish that HELQ interacts directly with the RAD51 paralog complex, BCDX2, and functions in parallel to the FA pathway to promote efficient HR at damaged replication forks. Thus, our results reveal a critical role for HELQ in replication-coupled DNA repair, germ cell maintenance and tumour suppression in mammals. 2013-09-04 2013-10-17 /pmc/articles/PMC3836231/ /pubmed/24005329 http://dx.doi.org/10.1038/nature12565 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Adelman, Carrie A. Lolo, Rafal L. Birkbak, Nicolai J. Murina, Olga Matsuzaki, Kenichiro Horejsi, Zuzana Parmar, Kalindi Borel, Valérie Skehel, J. Mark Stamp, Gordon D’Andrea, Alan Sartori, Alessandro A. Swanton, Charles Boulton, Simon J. HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title | HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title_full | HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title_fullStr | HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title_full_unstemmed | HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title_short | HELQ promotes RAD51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
title_sort | helq promotes rad51 paralog-dependent repair to avert germ cell attrition and tumourigenesis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836231/ https://www.ncbi.nlm.nih.gov/pubmed/24005329 http://dx.doi.org/10.1038/nature12565 |
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