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Helq acts in parallel to Fancc to suppress replication-associated genome instability

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 anemi...

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Detalles Bibliográficos
Autores principales: Luebben, Spencer W., Kawabata, Tsuyoshi, Akre, Monica K., Lee, Wai Long, Johnson, Charles S., O’Sullivan, M. Gerard, Shima, Naoko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905894/
https://www.ncbi.nlm.nih.gov/pubmed/24005041
http://dx.doi.org/10.1093/nar/gkt676
Descripción
Sumario: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.