Getting Ready for the Dance: FANCJ Irons Out DNA Wrinkles

Abstract

Mounting evidence indicates that alternate DNA structures, which deviate from normal double helical DNA, form in vivo and influence cellular processes such as replication and transcription. However, our understanding of how the cellular machinery deals with unusual DNA structures such as G-quadruplexes (G4), triplexes, or hairpins is only beginning to emerge. New advances in the field implicate a direct role of the Fanconi Anemia Group J (FANCJ) helicase, which is linked to a hereditary chromosomal instability disorder and important for cancer suppression, in replication past unusual DNA obstacles. This work sets the stage for significant progress in dissecting the molecular mechanisms whereby replication perturbation by abnormal DNA structures leads to genomic instability. In this review, we focus on FANCJ and its role to enable efficient DNA replication when the fork encounters vastly abundant naturally occurring DNA obstacles, which may have implications for targeting rapidly dividing cancer cells.

Keywords: FANCJ; Fanconi Anemia; G-quadruplex; cancer; genetic diseases; genomic instability; helicase; replication; secondary DNA structure.

Figure 1

FANCJ irons out G4 DNA Wrinkles. G-quadruplex (G4) DNA structures (inset) need to be resolved by G4-interacting proteins (e.g., FANCJ helicase) to provide a suitable template for replication and other DNA metabolic processes. Once FANCJ or other G4-interacting helicases remove the G4 DNA wrinkles, the protein machinery can smoothly copy, repair, or transcribe to maintain genomic stability and cellular homeostasis.

Figure 2

Proposed models for how FANCJ protein interactions provide a mechanistic opportunity to resolve G4 structures to enable smooth DNA synthesis. (A) FANCJ interacts with the TLS polymerase REV1 at the site of a G4 structure, enabling it to catalyze DNA synthesis past the G4 obstacle. A REV-1 interacting polymerase is likely to also be involved; (B) FANCJ interacts with the BLM (or WRN) helicase to efficiently resolve the G4 DNA structure, making the single-strand template accessible to a replicative DNA polymerase. For either model, the role of FANCJ may prevail for leading or lagging strand DNA synthesis. See text for details.