Fanconi anaemia and the repair of Watson and Crick DNA crosslinks

Abstract

The function of Fanconi anaemia proteins is to maintain genomic stability. Their main role is in the repair of DNA interstrand crosslinks, which, by covalently binding the Watson and the Crick strands of DNA, impede replication and transcription. Inappropriate repair of interstrand crosslinks causes genomic instability, leading to cancer; conversely, the toxicity of crosslinking agents makes them a powerful chemotherapeutic. Fanconi anaemia proteins can promote stem-cell function, prevent tumorigenesis, stabilize replication forks and inhibit inaccurate repair. Recent advances have identified endogenous aldehydes as possible culprits of DNA damage that may induce the phenotypes seen in patients with Fanconi anaemia.

Figure 1. The FA pathway functions in ICL repair

Upon detection of the crosslink, the core complex is activated and FANCL in the complex ubiquitylates the ID complex. The ID complex then coordinates the action of downstream repair factors, including nucleases and homologous recombination proteins, like the FA proteins BRCA2, FANCJ, PALB2, and RAD51C. Proteins that have been identified as mutated in FA patients are shown in color; factors known to participate in the pathway but are not clinically associated with FA are shown in grey. FANCJ, although not necessary for FANCD2 monoubiquitylation, may work at earlier steps than homologous recombination.

Figure 2. The diverse functions of the Fanconi anemia pathway

The Fanconi pathway has many roles in human biology: as a regulator of the maintenance and proliferation of hematopoietic stem and progenitor cells, a tumor suppressor pathway, a preserver of replication fork stability during S phase, and a barrier against unwanted mutagenic repair processes. Besides the hematopoietic cells, other stem cells are most likely being affected by lack of FA pathway leading to stochastic developmental abnormalities and the infertility in FA individuals.