Abstract
Microsatellites are short tandem repeat sequences that are highly prone to expansion/contraction due to their propensity to form non-B-form DNA structures, which hinder DNA polymerases and provoke template slippage. Although error correction by mismatch repair plays a key role in preventing microsatellite instability (MSI), which is a hallmark of Lynch syndrome, activities must also exist that unwind secondary structures to facilitate replication fidelity. Here, we report that Fancj helicase-deficient mice, while phenotypically resembling Fanconi anemia (FA), are also hypersensitive to replication inhibitors and predisposed to lymphoma. Whereas metabolism of G4-DNA structures is largely unaffected in Fancj(-/-) mice, high levels of spontaneous MSI occur, which is exacerbated by replication inhibition. In contrast, MSI is not observed in Fancd2(-/-) mice but is prevalent in human FA-J patients. Together, these data implicate FANCJ as a key factor required to counteract MSI, which is functionally distinct from its role in the FA pathway.
Highlights
Maintenance of genome integrity during DNA replication is of vital importance to ensure that daughter cells inherit an intact copy of the genetic code
Since Fancj-deficient cells are insensitive to G4-stabilizing drugs and are devoid of telomere fragility, we considered the possibility that FANCJ performs additional functions in genome stability independent of its role in the Fanconi anemia (FA) pathway and distinct from a role in G4-DNA metabolism
In the absence of any overt phenotype associated with G4-DNA metabolism in Fancj-deficient cells, we considered the possibility that problems associated with other types of DNA sequences/secondary structures are the cause of the replication defects in Fancj−/− mouse embryonic fibroblasts (MEFs)
Summary
Maintenance of genome integrity during DNA replication is of vital importance to ensure that daughter cells inherit an intact copy of the genetic code. Biochemical studies have shown that FANCJ unwinds a variety of DNA substrates, including 5′ flaps, forked duplexes, D loops, 5′ tailed triplexes, and G4-DNA structures in a 5′–3′ direction in vitro (Gupta et al 2005; London et al 2008; Wu et al 2008; Sommers et al 2009). Of these DNA structures, a clear picture has emerged linking FANCJ to the metabolism of G4-DNA secondary structures in vivo. Genome-wide transcription profiling of FANCJ knockout chicken DT40 cells has revealed that dys-
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