The Fanconi anemia protein interaction network: Casting a wide net

Abstract

It has long been hypothesized that a defect in the repair of damaged DNA is central to the etiology of Fanconi anemia (FA). Indeed, an increased sensitivity of FA patient-derived cells to the lethal effects of various forms of DNA damaging agents was described over three decades ago [1–3]. Furthermore, the cytological hallmark of FA, the DNA crosslink-induced radial chromosome formation, exemplifies an innate impairment in the repair of these particularly cytotoxic DNA lesions [4]. Precisely defining the collective role of the FA proteins in DNA repair, however, continues to be one of the most enigmatic and challenging questions in the FA field. The first six identified FA proteins (A, C, E, F, G, and D2) harbored no recognizable enzymatic features, precluding association with a specific metabolic process. Consequently, our knowledge of the role of the FA proteins in the DNA damage response has been gleaned primarily through biochemical association studies with non-FA proteins. Here, we provide a chronological discourse of the major FA protein interaction network discoveries, with particular emphasis on the DNA damage response, that have defined our current understanding of the molecular basis of FA.

The Fanconi anemia pathway and DNA interstrand cross-link repair

“…Studies of this disease have not only elucidated the general mechanisms of bone marrow failure, but also increased our knowledge of the molecular genetics and molecular pathogenesis of human cancers. Additionally, the Fanconi anemia pathway is a powerful model system for studying DNA damage signaling and tumorigenesis (Garcia-Higuera et al, 2001a;D'Andrea and Grompe, 2003;Kennedy and D'Andrea, 2005;Thompson et al, 2005;Wang, 2007;de Winter and Joenje, 2009;Rego et al, 2009). …”

DNA Repair Capacity and the Risk of Head and Neck Cancer

“…and combined functionally with FA repair pathway (Deakyne et al 2011;Rego et al,2009;Stoepker et al, 2011). However, their exact role have not yet been completely elucidated.…”

“…As result, FA cells demonstrate highly increased levels of chromosome aberrations, such as: chromosome breakages and radical forms of chromosomes (Auerbach, 1988;Li et al, 1999 (Fig.2). Homologous recombination is performed on the basis of homologous sequence on sister chromatids and the mechanism in itself is similar to crossing-over during meiosis (Deakyne et al, 2011,;Guervilly et al 2008;Machida et al, 2006;Rego et al, 2009;Takata et al, 2009). …”

Fancp/Slx4

“…7,8 The hallmark of FA patient cells, as well as BRCA1/2-deficient cells, is hypersensitivity to the clastogenic effects of DNA crosslinking agents, examples of which include mitomycin C (MMC) and cisplatin. 9 Indeed, the diagnostic test for FA is based directly upon this fact, and involves exposing FA patient cells to DNA crosslinking agents and scoring the percentage of metaphases exhibiting radial ©2 0 1 1 L a n d e s B i o s c i e n c e .…”