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XB-ART-49425
EMBO J November 3, 2014; 33 (21): 2521-33.
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FANCJ promotes DNA synthesis through G-quadruplex structures.

Castillo Bosch P , Segura-Bayona S , Koole W , van Heteren JT , Dewar JM , Tijsterman M , Knipscheer P .


Abstract
Our genome contains many G-rich sequences, which have the propensity to fold into stable secondary DNA structures called G4 or G-quadruplex structures. These structures have been implicated in cellular processes such as gene regulation and telomere maintenance. However, G4 sequences are prone to mutations particularly upon replication stress or in the absence of specific helicases. To investigate how G-quadruplex structures are resolved during DNA replication, we developed a model system using ssDNA templates and Xenopus egg extracts that recapitulates eukaryotic G4 replication. Here, we show that G-quadruplex structures form a barrier for DNA replication. Nascent strand synthesis is blocked at one or two nucleotides from the G4. After transient stalling, G-quadruplexes are efficiently unwound and replicated. In contrast, depletion of the FANCJ/BRIP1 helicase causes persistent replication stalling at G-quadruplex structures, demonstrating a vital role for this helicase in resolving these structures. FANCJ performs this function independently of the classical Fanconi anemia pathway. These data provide evidence that the G4 sequence instability in FANCJ(-/-) cells and Fancj/dog1 deficient C. elegans is caused by replication stalling at G-quadruplexes.

PubMed ID: 25193968
PMC ID: PMC4282361
Article link: EMBO J
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: ano1 brip1 fancd2
GO keywords: regulation of DNA biosynthetic process

Disease Ontology terms: Fanconi anemia complementation group J
OMIMs: FANCONI ANEMIA, COMPLEMENTATION GROUP J; FANCJ

Article Images: [+] show captions
References [+] :
Aguilera, Causes of genome instability. 2013, Pubmed