Elsevier

Experimental Cell Research

Volume 312, Issue 14, 15 August 2006, Pages 2647-2653
Experimental Cell Research

Review Article
The Fanconi anemia/BRCA pathway: A coordinator of cross-link repair

https://doi.org/10.1016/j.yexcr.2006.06.014Get rights and content

Abstract

Fanconi anemia (FA) is a rare inherited disease characterized by genomic instability and markedly increased cancer risk. Efforts to elucidate the molecular basis of FA have unearthed a novel DNA damage response pathway, the integrity of which is critical for cellular resistance to DNA cross-linking agents. Despite significant progress in uncovering the molecular events underlying FA, the precise function of this pathway in DNA repair is unknown. This article will review evidence implicating FA proteins in multiple aspects of DNA cross-link repair and propose a model to explain the selectivity of the FA pathway toward DNA cross-linking agents.

Section snippets

Fanconi anemia

Fanconi anemia (FA) is a multigenic autosomal and X-linked recessive syndrome characterized by congenital abnormalities, progressive bone marrow failure, and heightened cancer risk [1], [2]. At the cellular level, FA cells exhibit a striking hypersensitivity to DNA cross-linking agents such as cisplatin (CDDP) [3], mitomycin C (MMC) [4], and diepoxybutane (DEB) [5], a diagnostic hallmark of the syndrome. Somatic cell fusion studies and biochemical analyses have led to the identification of

DNA interstrand cross-link repair

DNA interstrand cross-links (ICLs) are extremely deleterious lesions caused by bi-functional alkylating agents that covalently tether both duplex DNA strands and pose formidable blocks to DNA metabolism. ICL forming compounds also constitute one of the most important classes of chemotherapeutic agents. ICL repair poses a unique challenge to cells as the covalent modification of both DNA strands renders simple excision and template-driven replication unfeasible. Our understanding of ICL repair

Fanconi anemia and nucleotide excision repair

The initial event in ICL repair is thought to entail the incision and uncoupling of the DNA cross-link, subsequently generating a monoadduct (Fig. 2.2). Consequently, mammalian cells demonstrate a dependence on the NER machinery for ICL repair. Unlike their yeast counterparts, however, not all NER proteins are required for cellular resistance to ICLs in mammals [14]. The NER endonucleases ERCC1/XPF can excise and uncouple ICLs at any stage in the cell cycle, as demonstrated by comet assays [15]

Fanconi anemia and homologous recombination

A critical step in ICL repair is the formation of a DNA DSB intermediate (Fig. 2.4), which explains the requirement for HR in the repair of such lesions [14], [15]. The discovery that biallelic mutations in BRCA2 caused Fanconi anemia and constituted the FA-D1 complementation group [11] was of primary importance in forging a link between the FA pathway and HR. Direct evidence for a function for FA proteins in HR repair has emerged from studies in human cells using plasmid-based recombination

Fanconi anemia and translesion synthesis

An intriguing phenotypic manifestation of Fanconi anemia patient-derived cells is their hypomutability for point mutations in response to monoadducts and ICLs [34]. Furthermore, FA cells displayed an increased incidence of large chromosomal insertions and deletions at the endogenous HPRT and ouabain loci, consistent with their observed chromosomal instability [35]. These observations have led to the supposition that the FA pathway normally facilitates an error-prone repair process that causes

Fanconi anemia and non-homologous end joining

Non-homologous DNA end joining (NHEJ) is the predominant pathway deployed by mammalian cells for DSB repair, particularly in the Go, G1, and early S cell cycle stages. NHEJ involves the joining of broken DNA ends via end processing and subsequent ligation. DNA end processing can result in the loss of a few nucleotides, often rendering the process of NHEJ imprecise [43]. Although ICL repair proceeds via a DSB intermediate as discussed above, NHEJ mutants generally do not exhibit ICL sensitivity

The Fanconi anemia pathway as a coordinator of cross-link repair

The FA pathway, particularly FANCD2, has been implicated in the regulation of cell cycle checkpoint responses, which could serve to facilitate repair. In addition to the well-characterized ATM kinase-mediated phosphorylation event at serine 222 [48], FANCD2 is phosphorylated on additional sites that regulate the S phase checkpoint response as well as cellular tolerance to MMC (Gary Ho and Alan D'Andrea, unpublished results). FA proteins may therefore constitute a signal transduction pathway

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