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FANCJ promotes DNA synthesis through G‐quadruplex structures
Author(s) -
Castillo Bosch Pau,
SeguraBayona Sandra,
Koole Wouter,
Heteren Jane T,
Dewar James M,
Tijsterman Marcel,
Knipscheer Puck
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201488663
Subject(s) - biology , g quadruplex , dna , dna binding protein , genetics , microbiology and biotechnology , computational biology , gene , transcription factor
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 ss DNA 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 / BRIP 1 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.