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The Fanconi anaemia pathway: newplayers and new functions
Raphael Ceccaldi, Prabha Sarangi and Alan D.DAndrea
Abstract | The Fanconi anaemia pathway repairs DNA interstrand crosslinks (ICLs) in the genome. Our understanding of this complex pathway is still evolving, as new components continue to be identified and new biochemical systems are used to elucidate the molecular steps of repair. TheFanconi anaemia pathway uses components of other known DNA repair processes to achieveproper repair of ICLs. Moreover, Fanconi anaemia proteins have functions in genome maintenance beyond their canonical roles of repairing ICLs. Such functions include the stabilization of replication forks and the regulation of cytokinesis. Thus, Fanconi anaemia proteins are emerging as master regulators of genomic integrity that coordinate several repair processes. Here, we summarize our current understanding of the functions of the Fanconi anaemia pathway in ICL repair, together with an overview of its connections with other repair pathways and its emerging roles in genome maintenance.
Cells are constantly challenged by DNA damage caused by exogenous and endogenous sources. During the past two decades, our understanding of how cells repair various types of DNA lesion to maintain genome integrity has greatly improved. Interstrand crosslinks (ICLs) are DNA lesions that inhibit essential processes such as replication and transcription, and they must be repaired or bypassed for the cell to survive. ICLs are also clinically relevant, as many chemotherapeutic regimens for the treatment of patients with cancer use agents that createICLs1.
In bacteria and eukaryotes, the major ICL repair pathway entails the combined actions of nucleotide excision repair and homologous recombination, with translesion synthesis making a minor contribution. In the past two decades, a unique genetic network that is specialized for ICL repair has been revealed through the characterization of the Fanconi anaemia pathway (also known as the Fanconi anaemia/BRCA pathway), with a few new players having been recently identified. The Fanconi anaemia pathway comprises 19 gene products (FANCA to FANCT). Germline inactivation of any one of the Fanconi anaemia genes causes Fanconi anaemia, a genetic disease that results in sensitivity to ICLs and predisposes patients to bone marrow failure and develop ment of cancer (BOXES1,2). The Fanconi anaemia pathway received considerable attention when one of the genes, FANCD1, was...