title: Helq acts in parallel to Fancc to suppress replication-associated genome instability.
abstract: HELQ is a superfamily 2 DNA helicase found in archaea and metazoans. It has been implicated in processing stalled replication forks and in repairing DNA double-strand breaks and inter-strand crosslinks. Though previous studies have suggested the possibility that HELQ is involved in the Fanconi anemia (FA) pathway, a dominant mechanism for inter-strand crosslink repair in vertebrates, this connection remains elusive. Here, we investigated this question in mice using the Helq(gt) and Fancc(-) strains. Compared with Fancc(-)(/)(-) mice lacking FANCC, a component of the FA core complex, Helq(gt/gt) mice exhibited a mild of form of FA-like phenotypes including hypogonadism and cellular sensitivity to the crosslinker mitomycin C. However, unlike Fancc(-)(/)(-) primary fibroblasts, Helq(gt/gt) cells had intact FANCD2 mono-ubiquitination and focus formation. Notably, for all traits examined, Helq was non-epistatic with Fancc, as Helq(gt)(/gt);Fancc(-)(/)(-) double mutants displayed significantly worsened phenotypes than either single mutant. Importantly, this was most noticeable for the suppression of spontaneous chromosome instability such as micronuclei and 53BP1 nuclear bodies, known consequences of persistently stalled replication forks. These findings suggest that mammalian HELQ contributes to genome stability in unchallenged conditions through a mechanism distinct from the function of FANCC.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA, Molecular, Cellular, Developmental Biology and Genetics Graduate Program, University of Minnesota, Minneapolis, MN 55455, USA, Masonic Cancer Center, Minneapolis, MN 55455, USA and College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Spencer W
authors.initials: SW
authors.lastname: Luebben
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Kawabata
authors.forename: Monica K
authors.initials: MK
authors.lastname: Akre
authors.forename: Wai Long
authors.initials: WL
authors.lastname: Lee
authors.forename: Charles S
authors.initials: CS
authors.lastname: Johnson
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.forename: Naoko
authors.initials: N
authors.lastname: Shima
mesh_terms: D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis; D003432:Cross-Linking Reagents / Q000633:toxicity; D004265:DNA Helicases / Q000032:analysis / Q000235:genetics*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000032:analysis; D004843:Epistasis, Genetic; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D005260:Female; D042822:Genomic Instability; D006130:Growth Disorders / Q000235:genetics; D059765:Homologous Recombination; D007006:Hypogonadism / Q000235:genetics; D007246:Infertility / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016685:Mitomycin / Q000633:toxicity; D010063:Ovum / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis; D016196:S Phase; D000071857:Tumor Suppressor p53-Binding Protein 1; D054875:Ubiquitination
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D003432:Cross-Linking Reagents; D004268:DNA-Binding Proteins; C498471:FANCA protein, human; C497651:FANCC protein, human; C497652:Fancc protein, mouse; D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D052236:Fanconi Anemia Complementation Group D2 Protein; D012333:RNA, Messenger; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D016685:Mitomycin; C584466:HELQ protein, mouse; D004265:DNA Helicases