Review ArticleThe Fanconi anemia/BRCA pathway: A coordinator of cross-link repair
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
References (50)
- et al.
A test for Fanconi's anemia
Blood
(1987) - et al.
Fanconi anemia (cross)linked to DNA repair
Cell
(2005) - et al.
The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly
J. Biol. Chem.
(2006) - et al.
Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway
Mol. Cell
(2001) - et al.
Repair of DNA interstrand cross-links
Mutat. Res.
(2001) - et al.
Defective DNA endonuclease activities in Fanconi's anemia cells, complementation groups A and B
Mutat. Res.
(1992) - et al.
The Fanconi anaemia gene FANCC promotes homologous recombination and error-prone DNA repair
Mol. Cell
(2004) - et al.
Role of BRCA2 in control of the RAD51 recombination and DNA repair protein
Mol. Cell
(2001) - et al.
Fanconi anemia complementation group D2 (FANCD2) functions independently of BRCA2- and RAD51-associated homologous recombination in response to DNA damage
J. Biol. Chem.
(2005) - et al.
Inducibility of nuclear Rad51 foci after DNA damage distinguishes all Fanconi anemia complementation groups from D1/BRCA2
Mutat. Res.
(2006)
Interaction of human DNA polymerase eta with monoubiquitinated PCNA: a possible mechanism for the polymerase switch in response to DNA damage
Mol. Cell
A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair
Mol. Cell
Tetratricopeptide-motif-mediated interaction of FANCG with recombination proteins XRCC3 and BRCA2
DNA Repair (Amst.)
Direct DNA binding activity of the Fanconi anemia D2 protein
J. Biol. Chem.
The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway
Mol. Cell
Fanconi anemia C gene product plays a role in the fidelity of blunt DNA end-joining
J. Mol. Biol.
Abnormal rearrangements associated with V(D)J recombination in Fanconi anemia
J. Mol. Biol.
Convergence of the Fanconi anemia and ataxia telangiectasia signaling pathways
Cell
The Fanconi anemia/BRCA pathway: new faces in the crowd
Genes Dev.
The Fanconi anaemia/BRCA pathway
Nat. Rev., Cancer
Differential sensitivity of Fanconi anaemia lymphocytes to the clastogenic action of cis-diamminedichloroplatinum (II) and trans-diamminedichloroplatinum (II)
Hum. Genet.
A test for Fanconi's anemia
Blood
A novel ubiquitin ligase is deficient in Fanconi anemia
Nat. Genet.
Functional interaction of monoubiquitinated FANCD2 and BRCA2/FANCD1 in chromatin
Mol. Cell. Biol.
Biallelic inactivation of BRCA2 in Fanconi anemia
Science
Cited by (71)
Cisplatin-induced DNA crosslinks trigger neurotoxicity in C. elegans
2024, Biochimica et Biophysica Acta - Molecular Cell ResearchA new frontier in Fanconi anemia: From DNA repair to ribosome biogenesis
2022, Blood ReviewsCitation Excerpt :Finally, the FANC/BRCA pathway exhibits broadest functions in genome integrity maintenance, including common fragile site protection [80ā82], transcription and R-loop homeostasis [83,84], telomere length maintenance [85,86] and mitotic cell division safeguards [87ā89]. In the 30 years of elegant cellular, molecular and biochemical studies that followed the cloning of the first FA-associated gene, FANCC, [90], the ālinearā FANC/BRCA pathway was extensively characterized and its centrality for genetic stability maintenance was thoroughly established [57ā59,79,88,91,92]. Thus, it has been proposed that the BMF in FA is caused by intrinsic HSC defects stemming from aberrancies in DNA repair and/or DDR.
Structural and functional relationships of FAN1
2017, DNA RepairCitation Excerpt :The first model is referred to as replication-coupled ICL repair, in which the Fanconi anemia (FA)-dependent incision of the ICL is a key event [13ā16]. This model requires four groups of proteins: structure-specific nucleases, translesion synthesis (TLS) DNA polymerases, as well as proteins in the homologous recombination (HR) and the FA pathways [17,18]. The model can be further divided depending on how forks encounter the ICL: the single fork convergence model when the fork collides at a single side of the ICL, and the dual fork convergence model when the forks are stalled on both sides of the ICL.
Pharmacological targeting of RAD6 enzyme-mediated translesion synthesis overcomes resistance to platinum-based drugs
2017, Journal of Biological ChemistryCitation Excerpt :Our data from Fig. 2 showed that treatment with SMI#9 or RAD6B siRNA results in a decrease in cisplatin-induced PCNA and FANCD2 monoubiquitinations and overall steady-state levels of FANCD2. During repair of ICLs, FANCD2, PCNA, and TLS DNA POL Ī· play important roles in restart of replicating forks at the damage site (37). Formation of FANCD2 foci is suggested to mark the site of cisplatin damage in the chromatin and in combination with PCNA and TLS polymerase POL Ī· to play a role in resolution of stalled replication forks (38, 39).
Sequence conversion by single strand oligonucleotide donors via non-homologous end joining in mammalian cells
2010, Journal of Biological ChemistryCitation Excerpt :We were curious about the influence of repair functions in SSO-mediated sequence conversion. Genes of particular interest were components of the FA/BRCA pathway, which have been implicated in both cross-link (70, 71) and DSB repair, including NHEJ (72, 73) and HDR pathways (74). Thus we examined the activity of the SSO-0 and the 200-nt 2nd step deletion donor in cells with mutant or impaired FA and HDR proteins.