The Fanconi anemia protein interaction network: casting a wide net - PubMed (original) (raw)

Review

The Fanconi anemia protein interaction network: casting a wide net

Meghan A Rego et al. Mutat Res. 2009.

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 [A.J. Fornace, Jr., J.B. Little, R.R. Weichselbaum, DNA repair in a Fanconi's anemia fibroblast cell strain, Biochim. Biophys. Acta 561 (1979) 99-109; Y. Fujiwara, M. Tatsumi, Repair of mitomycin C damage to DNA in mammalian cells and its impairment in Fanconi's anemia cells, Biochem. Biophys. Res. Commun. 66 (1975) 592-598; A.J. Rainbow, M. Howes, Defective repair of ultraviolet- and gamma-ray-damaged DNA in Fanconi's anaemia, Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 31 (1977) 191-195]. 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 [A.D. Auerbach, Fanconi anemia diagnosis and the diepoxybutane (DEB) test, Exp. Hematol. 21 (1993) 731-733]. 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.

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Figures

Fig. 1

Fig. 1

A graphical overview of the FA protein interaction network. The network is superimposed on the Massachusetts Bay Transportation Authority (MBTA) T map in recognition of where many of the FA protein interactions were discovered. This complex network is comprised of thirteen FA gene-encoded proteins as well as at least twenty-seven non-FA proteins. While a different biological function is depicted for each line, these functions are often overlapping, with many proteins playing important roles in several cellular functions. Light grey lines depict known or putative protein-protein interactions. TLS, translesion DNA synthesis. IR, ionizing radiation.

Fig. 2

Fig. 2

Models depicting the proposed functions of the FA protein interaction network in the repair of stalled or collapsed DNA replication forks. Upon encounter of a DNA lesion on the template strand during DNA replication several options are possible. (A) To ensure timely replication fork progression, the template strand DNA lesion can be bypassed in an error-prone REV1- and/or DNA Pol ζ-dependent TLS mechanism. The FA core complex is required for the assembly of REV1 nuclear foci, suggesting that the FA core complex may specifically promote error-prone REV1-dependent TLS. This pathway appears to be independent of both PCNA and FANCD2 mono-ubiquitination. The molecular details of FA core complex promoted REV1-dependent TLS remain to be fully elucidated. (B) The DNA replisome may arrest at the lesion and subsequently resume DNA synthesis downstream of the lesion. The ensuing post-replicative gap (or daughter-strand gap) may be repaired by a combined HR/TLS PCNA mono-ubiqutination-dependent mechanism. We propose that the mono-ubiquitination of FANCD2 and FANCI may also be required for this process by an as-yet-undefined mechanism.

Fig. 2

Fig. 2

Models depicting the proposed functions of the FA protein interaction network in the repair of stalled or collapsed DNA replication forks. Upon encounter of a DNA lesion on the template strand during DNA replication several options are possible. (A) To ensure timely replication fork progression, the template strand DNA lesion can be bypassed in an error-prone REV1- and/or DNA Pol ζ-dependent TLS mechanism. The FA core complex is required for the assembly of REV1 nuclear foci, suggesting that the FA core complex may specifically promote error-prone REV1-dependent TLS. This pathway appears to be independent of both PCNA and FANCD2 mono-ubiquitination. The molecular details of FA core complex promoted REV1-dependent TLS remain to be fully elucidated. (B) The DNA replisome may arrest at the lesion and subsequently resume DNA synthesis downstream of the lesion. The ensuing post-replicative gap (or daughter-strand gap) may be repaired by a combined HR/TLS PCNA mono-ubiqutination-dependent mechanism. We propose that the mono-ubiquitination of FANCD2 and FANCI may also be required for this process by an as-yet-undefined mechanism.

References

    1. Fornace AJ, Jr, Little JB, Weichselbaum RR. DNA repair in a Fanconi’s anemia fibroblast cell strain. Biochim Biophys Acta. 1979;561:99–109. - PubMed
    1. Fujiwara Y, Tatsumi M. Repair of mitomycin C damage to DNA in mammalian cells and its impairment in Fanconi’s anemia cells. Biochem Biophys Res Commun. 1975;66:592–598. - PubMed
    1. Rainbow AJ, Howes M. Defective repair of ultraviolet- and gamma-ray-damaged DNA in Fanconi’s anaemia. Int J Radiat Biol Relat Stud Phys Chem Med. 1977;31:191–195. - PubMed
    1. Auerbach AD. Fanconi anemia diagnosis and the diepoxybutane (DEB) test. Exp Hematol. 1993;21:731–733. - PubMed
    1. Baumann P, West SC. Role of the human RAD51 protein in homologous recombination and double-stranded-break repair. Trends Biochem Sci. 1998;23:247–251. - PubMed

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