Review
The Fanconi anemia pathway: Repairing the link between DNA damage and squamous cell carcinoma

https://doi.org/10.1016/j.mrfmmm.2013.01.001Get rights and content

Abstract

Fanconi anemia (FA) is a rare inherited recessive disease caused by mutations in one of fifteen genes known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into high molecular weight complexes through a cascade of post-translational modifications and physical interactions, followed by the repair of damaged DNA. Hematopoietic cells are particularly sensitive to the loss of these interactions, and bone marrow failure occurs almost universally in FA patients. FA as a disease is further characterized by cancer susceptibility, which highlights the importance of the FA pathway in tumor suppression, and will be the focus of this review. Acute myeloid leukemia is the most common cancer type, often subsequent to bone marrow failure. However, FA patients are also at an extreme risk of squamous cell carcinoma (SCC) of the head and neck and gynecological tract, with an even greater incidence in those individuals who have received a bone marrow transplant and recovered from hematopoietic disease. FA tumor suppression in hematopoietic versus epithelial compartments could be mechanistically similar or distinct. Definition of compartment specific FA activities is now critical to assess the effects of today's bone marrow failure treatments on tomorrow's solid tumor development. It is our hope that current therapies can then be optimized to decrease the risk of malignant transformation in both hematopoietic and epithelial cells. Here we review our current understanding of the mechanisms of action of the Fanconi anemia pathway as it contributes to stress responses, DNA repair and squamous cell carcinoma susceptibility.

Section snippets

Fanconi anemia pathway mutations play key role in the development of cancer

FA is a rare, autosomal recessive, and X-linked in the case of FANCB, syndrome characterized by congenital defects, bone marrow failure (BMF), and increased susceptibility to cancers. These are predominantly acute myeloid leukemia (AML) and head and neck squamous cell carcinoma (HNSCC) [1], [2], [3], [4]. Disease incidence is rare, estimated at 1 in 200,000 live births, with a carrier frequency of 1 in 181 [5], [6]. A diagnosis of FA is devastating with a median life expectancy of a little over

The FA pathway: multi-protein interactions coordinate DNA repair

Fifteen complementation groups and the corresponding FA genes have now been identified [14], [22], [23], [24], [26], [27], [33], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63]. Their protein products function as either signal transducers and/or DNA processing factors within the larger FA-BRCA DNA damage response network as described below. Our published studies have demonstrated that multiple FA and associated genes are transcriptionally limiting and

Clonal evolution plays a key role in progression to leukemia in the FA population

A majority of FA patients invariably experience progressive bone marrow failure (BMF), and oftentimes leukemia [5], [41], [98], [99], [100]. Marrow dysfunction occurs at approximately 7–8 years old, is associated with stem cell loss in the hematopoietic compartment, and is responsible for the majority of FA childhood mortality (for a review see [101]). The risk of BMF in FA is 90 percent by 50 years of age, although the mechanism for stem cell loss is not fully understood [3]. Rapid

Mutations in the FA pathway lead to increased risk of squamous cell carcinoma

Results from the International FA Registry (IFAR) have revealed that FA patients are highly susceptible to non-hematologic neoplasms [3], [98]. Squamous cell carcinomas (SCCs) of the anogenital region and head and neck, the latter with an up to 1400 fold risk over that of the normal population, are the most commonly diagnosed solid tumors in these patients. A recent report on cancer incidence in the German FA Registry also described an extreme risk of head and neck, vulvar, and esophageal SCC

Oncogenicity: a selection driven or active process in the FA population?

The onset of cancers, such as leukemia and squamous cell carcinoma (SCC), takes place at an unusually early age in persons with FA when compared to control populations. The observed accelerated transformation of FA hematopoietic cells to leukemia, and that of keratinocytes to SCC, may occur through similar or distinct molecular mechanisms. Recent unpublished data generated in our lab indicate that at the level of gene regulation, several pathways specific to epithelial (rather than

Disease biomarker discovery for FA-associated HNSCC

Individuals with sporadic HNSCC frequently present at advanced disease stages, which is a direct result of inferior diagnostic approaches, and necessitates aggressive chemo- and/or radiation therapy [177]. The downside of this scenario in FA patients diagnosed with HNSCC is that these therapeutic methods typically lead to extreme toxicity and sometimes death [128], [131], [132]. To add to the complexity of the situation, in over 20% of FA patients diagnosed with a solid tumor, a diagnosis of FA

Conflict of interest statement

The authors declare that there are no conflicts of interest

Acknowledgements

Research on Fanconi anemia in the Wells laboratory was supported by a Public Health Service Grant CA102357, and by a grant from the Fanconi Anemia Research Fund. We thank Elizabeth Hoskins and Drs. Paul Andreassen, Kasiani Myers, Timothy Chlon and Lisa Privette Vinnedge for critical comments on this report.

References (194)

  • I. Garcia-Higuera et al.

    Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway

    Mol. Cell

    (2001)
  • M.S. van der Heijden et al.

    Functional defects in the fanconi anemia pathway in pancreatic cancer cells

    Am. J. Pathol.

    (2004)
  • E.R. Snyder et al.

    Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines

    Cancer Lett.

    (2007)
  • K. Burkitt et al.

    Fanconi anemia response due to BRCA1 deficiency in cisplatin-sensitive head and neck cancer cell lines

    Cancer Lett.

    (2007)
  • J.P. de Winter et al.

    Isolation of a cDNA representing the Fanconi anemia complementation group E gene

    Am. J. Hum. Genet.

    (2000)
  • C. Timmers et al.

    Positional cloning of a novel Fanconi anemia gene, FANCD2

    Mol. Cell

    (2001)
  • A. Ciccia et al.

    Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM

    Mol. Cell

    (2007)
  • A.M. Ali et al.

    FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein required for functional integrity of the FA-BRCA DNA repair pathway

    Blood

    (2012)
  • N.B. Collins et al.

    ATR-dependent phosphorylation of FANCA on serine 1449 after DNA damage is important for FA pathway function

    Blood

    (2009)
  • F. Qiao et al.

    Phosphorylation of fanconi anemia (FA) complementation group G protein, FANCG, at serine 7 is important for function of the FA pathway

    J. Biol. Chem.

    (2004)
  • Y.J. Machida et al.

    UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation

    Mol. Cell

    (2006)
  • T.R. Singh et al.

    Impaired FANCD2 monoubiquitination and hypersensitivity to camptothecin uniquely characterize Fanconi anemia complementation group M

    Blood

    (2009)
  • T.R. Singh et al.

    MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM

    Mol. Cell

    (2010)
  • J.M. Kim et al.

    Cell cycle-dependent chromatin loading of the Fanconi anemia core complex by FANCM/FAAP24

    Blood

    (2008)
  • M. Takata et al.

    The Fanconi anemia pathway: insights from somatic cell genetics using DT40 cell line

    Mutat. Res.

    (2009)
  • C. MacKay et al.

    Identification of KIAA1018/FAN1, a DNA repair nuclease recruited to DNA damage by monoubiquitinated FANCD2

    Cell

    (2010)
  • A. Smogorzewska et al.

    A genetic screen identifies FAN1, a Fanconi anemia-associated nuclease necessary for DNA interstrand crosslink repair

    Mol. Cell

    (2010)
  • L. O‘Donnell et al.

    DNA repair has a new FAN1 club

    Mol. Cell

    (2010)
  • S.M. Nijman et al.

    The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway

    Mol. Cell

    (2005)
  • V.H. Oestergaard et al.

    Deubiquitination of FANCD2 is required for DNA crosslink repair

    Mol. Cell

    (2007)
  • J.M. Kim et al.

    Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype

    Dev. Cell

    (2009)
  • B.P. Alter

    Fanconi's anemia and malignancies

    Am. J. Hematol.

    (1996)
  • H. Joenje et al.

    The emerging genetic and molecular basis of Fanconi anaemia

    Nat. Rev. Genet.

    (2001)
  • P.S. Rosenberg et al.

    How high are carrier frequencies of rare recessive syndromes? Contemporary estimates for Fanconi Anemia in the United States and Israel

    Am. J. Med. Genet. A

    (2011)
  • A. Rochowski et al.

    Patients with Fanconi anemia and AML have different cytogenetic clones than de novo cases of AML

    Pediatr. Blood Cancer

    (2012)
  • F. Zhang et al.

    FANCJ/BRIP1 recruitment and regulation of FANCD2 in DNA damage responses

    Chromosoma

    (2010)
  • I.Y. Song et al.

    A novel role for Fanconi anemia (FA) pathway effector protein FANCD2 in cell cycle progression of untransformed primary human cells

    Cell Cycle

    (2010)
  • K. Sato et al.

    Histone chaperone activity of Fanconi anemia proteins, FANCD2 and FANCI, is required for DNA crosslink repair

    EMBO J.

    (2012)
  • M.S. Sasaki

    Is Fanconi's anaemia defective in a process essential to the repair of DNA cross links?

    Nature

    (1975)
  • A.D. Auerbach

    A test for Fanconi's anemia

    Blood

    (1988)
  • M.S. Sasaki et al.

    A high susceptibility of Fanconi's anemia to chromosome breakage by DNA cross-linking agents

    Cancer Res.

    (1973)
  • A.D. Auerbach

    Fanconi anemia diagnosis and the diepoxybutane (DEB) test

    Exp. Hematol.

    (1993)
  • W. Wang

    A major switch for the Fanconi anemia DNA damage-response pathway

    Nat. Struct. Mol. Biol.

    (2008)
  • P.R. Andreassen et al.

    ATR couples FANCD2 monoubiquitination to the DNA-damage response

    Genes Dev.

    (2004)
  • N.G. Howlett et al.

    Biallelic inactivation of BRCA2 in Fanconi anemia

    Science

    (2002)
  • B. Xia et al.

    Fanconi anemia is associated with a defect in the BRCA2 partner PALB2

    Nat. Genet.

    (2007)
  • S. Reid et al.

    Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer

    Nat. Genet.

    (2006)
  • M. Levitus et al.

    The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J

    Nat. Genet.

    (2005)
  • O. Levran et al.

    The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia

    Nat. Genet.

    (2005)
  • W. Wang

    Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins

    Nat. Rev. Genet.

    (2007)
  • Cited by (0)

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