Publication Date:
2013-09-06
Description:
Repair of interstrand crosslinks (ICLs) requires the coordinated action of the intra-S-phase checkpoint and the Fanconi anaemia pathway, which promote ICL incision, translesion synthesis and homologous recombination (reviewed in refs 1, 2). Previous studies have implicated the 3'-5' superfamily 2 helicase HELQ in ICL repair in Drosophila melanogaster (MUS301 (ref. 3)) and Caenorhabditis elegans (HELQ-1 (ref. 4)). Although in vitro analysis suggests that HELQ preferentially unwinds synthetic replication fork substrates with 3' single-stranded DNA overhangs and also disrupts protein-DNA interactions while translocating along DNA, 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 paralogue complex BCDX2 and functions in parallel to the Fanconi anaemia pathway to promote efficient homologous recombination 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836231/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836231/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adelman, Carrie A -- Lolo, Rafal L -- Birkbak, Nicolai J -- Murina, Olga -- Matsuzaki, Kenichiro -- Horejsi, Zuzana -- Parmar, Kalindi -- Borel, Valerie -- Skehel, J Mark -- Stamp, Gordon -- D'Andrea, Alan -- Sartori, Alessandro A -- Swanton, Charles -- Boulton, Simon J -- A3549/Cancer Research UK/United Kingdom -- R01 DK043889/DK/NIDDK NIH HHS/ -- R01-DK43889/DK/NIDDK NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 Oct 17;502(7471):381-4. doi: 10.1038/nature12565. Epub 2013 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms EN6 3LD, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24005329" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*Carcinogenesis/genetics/pathology
;
DNA Damage/genetics
;
DNA Helicases/deficiency/genetics/*metabolism
;
*DNA Repair/genetics
;
DNA Replication/genetics
;
Fanconi Anemia/metabolism
;
Fanconi Anemia Complementation Group D2 Protein/deficiency/genetics/metabolism
;
Female
;
Gene Deletion
;
Germ Cells/cytology/*metabolism/*pathology
;
Male
;
Mice
;
Multiprotein Complexes/metabolism
;
Ovarian Neoplasms/genetics/metabolism/pathology
;
Ovary/metabolism/pathology
;
Rad51 Recombinase/*metabolism
;
Recombinational DNA Repair/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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