Fanconi Anemia DNA Repair Research Articles

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

Highlights of This Issue

Hypoxia generates genomic instability via replication stress and dysregulation of critical DNA repair mechanisms. The Fanconi anemia (FA) DNA repair proteins are key players in the response to replicative stress, yet their regulation under hypoxia has not been delineated. This study, reported by Scanlon and Glazer, demonstrates that acute hypoxic stress activates the FA pathway and that this activation plays an important role in maintaining genomic integrity and cell survival during hypoxia. In addition, prolonged hypoxia induces transcriptional repression of FA proteins, revealing a novel weakness of cells under chronic hypoxia. These findings identify the FA pathway as a therapeutic target in the hypoxic tumor microenvironment.Anaplastic thyroid carcinoma is one of the most aggressive kinds of human cancer, and no significant treatments are available. Patients succumb so rapidly that recruitment of clinical cohorts is a challenge, making mouse models invaluable. Charles and colleagues modeled the combined expression of BRAFV600E and PIK3CAH1074R in the thyroids of mice. Critically, these activating mutations cooperate to promote tumor progression from papillary to anaplastic thyroid carcinoma. This model uses clinically relevant mutations that can be pharmacologically targeted and presents striking similarities to the human disease; therefore, it is ideal for preclinical studies. Furthermore, these mutations are relevant in other human cancers, such as melanoma and lung.Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options and a fatal prognosis. Cases of GBM often display a deregulated apoptotic pathway. Pareja and colleagues use the Bcl-2 inhibitor ABT-263 alone or in combination with GDC-0941, a PI3K inhibitor, to treat established GBMs and GBM neurospheres. Mechanistically, GDC-0941 lowers Mcl-1 protein levels, a Bcl-2 family protein that renders GBMs resistant to ABT-263. In turn, GDC-0941 broadly sensitizes GBMs to the cytotoxic effects of ABT-263. Thus, combination therapy with ABT-263 and GDC-0941 represents a novel therapeutic strategy by overcoming endogenous resistance to apoptosis.This study identifies pIRF3S386 as a biomarker of TBK1 activity in cancer cell lines. Muvaffak and colleagues examined the synthetic lethal interaction of TBK1 inhibition with mutant KRAS in a panel of cancer cell lines. Their study demonstrates that pIRF3S386 could be a useful tool for identification of effective TBK1 pathway inhibition in PDAC cell lines. They found that reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors in KRAS-mutant cancer cells did not correlate with reduced proliferation. These findings suggest that regulation of signaling pathways important for cell proliferation in KRAS-mutant cancer cells is not solely dependent on TBK1 activity.

Prevalence and outcome of mutations (mut) in the Fanconi anemia (FA) DNA repair pathway among head and neck cancer (H&N Ca) patients (pts).

6036 Background: Almost all survivors of FA, an inherited DNA repair deficiency syndrome, will develop H&N Ca. Preclinical data in H&N Ca cells harboring FA mut show increased sensitivity to chemo ...

The Fanconi Anemia DNA Repair Pathway: Structural and Functional Insights into a Complex Disorder

Mutations in any of at least sixteen FANC genes (FANCA-Q) cause Fanconi anemia, a disorder characterized by sensitivity to DNA interstrand crosslinking agents. The clinical features of cytopenia, developmental defects, and tumor predisposition are similar in each group, suggesting that the gene products participate in a common pathway. The Fanconi anemia DNA repair pathway consists of an anchor complex that recognizes damage caused by interstrand crosslinks, a multisubunit ubiquitin ligase that monoubiquitinates two substrates, and several downstream repair proteins including nucleases and homologous recombination enzymes. We review progress in the use of structural and biochemical approaches to understanding how each FANC protein functions in this pathway.

The Carboxyl Terminus of FANCE Recruits FANCD2 to the Fanconi Anemia (FA) E3 Ligase Complex to Promote the FA DNA Repair Pathway

Fanconi anemia (FA) is a genome instability syndrome characterized by bone marrow failure and cellular hypersensitivity to DNA cross-linking agents. In response to DNA damage, the FA pathway is activated through the cooperation of 16 FA proteins. A central player in the pathway is a multisubunit E3 ubiquitin ligase complex or the FA core complex, which monoubiquitinates its substrates FANCD2 and FANCI. FANCE, a subunit of the FA core complex, plays an essential role by promoting the integrity of the complex and by directly recognizing FANCD2. To delineate its role in substrate ubiquitination from the core complex assembly, we analyzed a series of mutations within FANCE. We report that a phenylalanine located at the highly conserved extreme C terminus, referred to as Phe-522, is a critical residue for mediating the monoubiquitination of the FANCD2-FANCI complex. Using the FANCE mutant that specifically disrupts the FANCE-FANCD2 interaction as a tool, we found that the interaction-deficient mutant conferred cellular sensitivity in reconstituted FANCE-deficient cells to a similar degree as FANCE null cells, suggesting the significance of the FANCE-FANCD2 interaction in promoting cisplatin resistance. Intriguingly, ectopic expression of the FANCE C terminus fragment alone in FA normal cells disrupts DNA repair, consolidating the importance of the FANCE-FANCD2 interaction in the DNA cross-link repair.

Acetaldehyde and the genome: Beyond nuclear DNA adducts and carcinogenesis

The designation of acetaldehyde associated with the consumption of alcoholic beverages as "carcinogenic to humans" (Group 1) by the International Agency for Research on Cancer (IARC) has brought renewed attention to the biological effects of acetaldehyde, as the primary oxidative metabolite of alcohol. Therefore, the overall focus of this review is on acetaldehyde and its direct and indirect effects on the nuclear and mitochondrial genome. We first consider different acetaldehyde-DNA adducts, including a critical assessment of the evidence supporting a role for acetaldehyde-DNA adducts in alcohol related carcinogenesis, and consideration of additional data needed to make a conclusion. We also review recent data on the role of the Fanconi anemia DNA repair pathway in protecting against acetaldehyde genotoxicity and carcinogenicity, as well as teratogenicity. We also review evidence from the older literature that acetaldehyde may impact the genome indirectly, via the formation of adducts with proteins that are themselves critically involved in the maintenance of genetic and epigenetic stability. Finally, we note the lack of information regarding acetaldehyde effects on the mitochondrial genome, which is notable since aldehyde dehydrogenase 2 (ALDH2), the primary acetaldehyde metabolic enzyme, is located in the mitochondrion, and roughly 30% of East Asian individuals are deficient in ALDH2 activity due to a genetic variant in the ALDH2 gene. In summary, a comprehensive understanding of all of the mechanisms by which acetaldehyde impacts the function of the genome has implications not only for alcohol and cancer, but types of alcohol related pathologies as well.

Fancd2 Deficiency Impairs Autophagy Via Deregulating The Ampk/Foxo3a/Akt Pathway

Fanconi anemia (FA) is a genetic disease characterized by bone narrow failure and high risk of malignancy. The disease is due to a deficiency in the FA DNA repair pathway. Impaired function of the FA pathway leads to a decrease in survival, self-renewal and function of hematopoietic stem cells (HSCs). Previous reports have shown that FOXO3a directs a protective autophagy program for HSCs. Autophagy is an intracellular degradation system that enables cell to survive during stress like nutriment deprivation or oxidative stress by recycling damage proteins and organelles like mitochondria. Our laboratory has shown that FA-deficient cells are hypersensitive to oxidative stress and that FANCD2/FOXO3a interaction directs anti-oxidative response and cell survival. The FANCD2/FOXO3a axis could play a role in the protective autophagy activity in HSCs. For these reasons, we decided to study autophagy in the context of FANCD2-deficient (FA-D2) human lymphoblast cells exposed to oxidative stress. Interestingly, we observed an impaired activation of autophagy in the FA-D2 cells, detected by LC3-II immunoblot and flow cytometry, compared to FANCD2-corrected (control) cells. We found an increased necroapoptosis as soon as 1 hour after H2O2 treatment in FA-D2 cells. Paradoxically, we observed a profound decrease in the activity of the mTORC1 complex (as determined by S6 and S6k1 phosphorylation) in FA-D2 cells. In order to explain this autophagy deregulation, we determined the activation of AKT known to up-regulate mTORC1 activity. AKT activation (monitored by phospho-ser473) was significantly decreased in FA-D2 cells compared to control cells. Consequently, FOXO3a was over-activated in FA-D2 cells after H2O2 treatment. Consistently, we found markedly increased activation of AMPK known to initiate and sustain FOXO3a activation. Since AKT controls the expression of p62/SQSTM1, a protein involved in autophagy by addressing the damaged proteins/organelles to autophagic vesicles, we next examined the level of p62 in FA-D2 cells. In contradiction with the impaired autophagy in FA-D2 cells, we observed a decrease of p62 protein compared to corrected cells. To ensure that p62 protein decrease was not due to autophagy activity, we examined p62 transcription and found that the level of p62 mRNA was significantly decreased in FA-D2 cells. Our study thus identifies a deregulated AMPK/FOXO3a/AKT pathway in FA hematopoietic cells, and reveals an impaired autophagy process in which over-activated AMPK initiates FOXO3a activation that in turn inactivates AKT leading to down-regulation of p62. Thus, impaired autophagy may play a causal role in the hypersensitivity of FA-deficient cells to oxidative stress. Disclosures:No relevant conflicts of interest to declare.

Inactivation of Uaf1 Causes Defective Homologous Recombination and Early Embryonic Lethality in Mice

The deubiquitinating enzyme heterodimeric complex USP1-UAF1 regulates the Fanconi anemia (FA) DNA repair pathway. Absence of this complex leads to increased cellular levels of ubiquitinated FANCD2 (FANCD2-Ub) and ubiquitinated PCNA (PCNA-Ub). Mice deficient in the catalytic subunit of the complex, USP1, exhibit an FA-like phenotype and have a cellular deficiency in homologous-recombination (HR) repair. Here, we have characterized mice deficient in the UAF1 subunit. Uaf1(+/-) mice were small at birth and exhibited reduced fertility, thus resembling Usp1(-/-) mice. Unexpectedly, homozygous Uaf1(-/-) embryos died at embryonic day 7.5 (E7.5). These mutant embryos were small and developmentally retarded. As expected, Uaf1 deficiency in mice led to increased levels of cellular Fancd2-Ub and Pcna-Ub. Uaf1(+/-) murine embryonic fibroblasts (MEFs) exhibited profound chromosome instability, genotoxin hypersensitivity, and a significant defect in homologous-recombination repair. Moreover, Uaf1(-/-) mouse embryonic stem cells (mESCs) showed chromosome instability, genotoxin hypersensitivity, and impaired Fancd2 focus assembly. Similar to USP1 knockdown, UAF1 knockdown in tumor cells caused suppression of tumor growth in vivo. Taken together, our data demonstrate the important regulatory role of the USP1-UAF1 complex in HR repair through its regulation of the FANCD2-Ub and PCNA-Ub cellular pools.

Toxic Metabolism and DNA Repair and Haematopoesis

Recent work from my lab has discovered that metabolism generates reactive aldehydes. These reactive molecules are potent at damaging DNA, and the consequences of this are revealed by the combined inactivation of enzymes that detoxify these aldehydes and the Fanconi anemia DNA repair pathway in mice and vertebrate cell lines. I shall discuss this work and recent unpublished work on how natural aldehydes damage blood stem cells. This work has consequences for understanding how metabolism and ethanol exposure can be genotoxic particularly in the vast population of southeast Asians carrying a genetic defect in aldehyde catabolism ( “pink flushers”) and also in the emergence of bone marrow failure and leukaemia in Fanconi Anaemia.

Links Between DNA Damage and Metabolism, Pathways Causing Bone Marrow Failure in Fanconi Anemia, and Therapeutic Implications

AbstractAbstract SCI-3Recent work from my lab has discovered that metabolism generates reactive aldehydes. These reactive molecules are potent damagers of DNA. The consequences of this are revealed by the inactivation of enzymes that detoxify these aldehydes and the Fanconi anemia DNA repair pathway in mice and vertebrate cell lines. The scientific session presentation will discuss this work and recent unpublished research on how natural aldehydes damage blood stem cells. This work has consequences for understanding how metabolism and ethanol exposure can be genotoxic, particularly in the vast population of Southeast Asians carrying a genetic defect in aldehyde catabolism (“pink flushers”). It is also relevant to the emergence of bone marrow failure and leukemia in Fanconi anemia. Disclosures:No relevant conflicts of interest to declare.

Oxidation-Mediated DNA Cross-Linking Contributes to the Toxicity of 6-Thioguanine in Human Cells

The thiopurines azathioprine and 6-mercaptopurine have been extensively prescribed as immunosuppressant and anticancer agents for several decades. A third member of the thiopurine family, 6-thioguanine (6-TG), has been used less widely. Although known to be partly dependent on DNA mismatch repair (MMR), the cytotoxicity of 6-TG remains incompletely understood. Here, we describe a novel MMR-independent pathway of 6-TG toxicity. Cell killing depended on two properties of 6-TG: its incorporation into DNA and its ability to act as a source of reactive oxygen species (ROS). ROS targeted DNA 6-TG to generate potentially lethal replication-arresting DNA lesions including interstrand cross-links. These triggered processing by the Fanconi anemia and homologous recombination DNA repair pathways. Allopurinol protected against 6-TG toxicity by acting as a ROS scavenger and preventing DNA damage. Together, our findings provide mechanistic evidence to support the proposed use of thiopurines to treat HR-defective tumors and for the coadministration of 6-TG and allopurinol as an immunomodulation strategy in inflammatory disorders.

A Ubiquitin-Binding Protein, FAAP20, Links RNF8-Mediated Ubiquitination to the Fanconi Anemia DNA Repair Network

The Fanconi anemia (FA) protein network is necessary for repair of DNA interstrand crosslinks (ICLs), but its control mechanism remains unclear. Here we show that the network is regulated by a ubiquitin signaling cascade initiated by RNF8 and its partner, UBC13, and mediated by FAAP20, a component of the FA core complex. FAAP20 preferentially binds the ubiquitin product of RNF8-UBC13, and this ubiquitin-binding activity and RNF8-UBC13 are both required for recruitment of FAAP20 to ICLs. Both RNF8 and FAAP20 are required for recruitment of FA core complex and FANCD2 to ICLs, whereas RNF168 can modulate efficiency of the recruitment. RNF8 and FAAP20 are needed for efficient FANCD2 monoubiquitination, a key step of the FA network; RNF8 and the FA core complex work in the same pathway to promote cellular resistance to ICLs. Thus, the RNF8-FAAP20 ubiquitin cascade is critical for recruiting FA core complex to ICLs and for normal function of the FA network.

PD10-01: Prevalence of Dysfunctional Fanconi Anemia (FA) DNA Repair Pathway in Breast Cancer.

Abstract Purpose: BRCA1/2 deficient breast tumors are highly sensitive to poly- ADP-ribose polymerase inhibitors (PARPi). The Fanconi Anemia (FA) associated gene products along with BRCA 1/2 function in a common pathway that regulates the cellular response to DNA damage, suggesting that tumors with dysfunction of any of the components of FA network would be susceptible to PARPi. Understanding the prevalence of such defects in breast tumors using reproducible methodology will help us target these tumors with novel agents and potentially improve outcomes. Hence we sought to assess the prevalence of FA pathway defect in breast tumors by the absence of nuclear FANCD2 (a pivotal protein in the FA/BRCA pathway which is monoubiquitylated in the nucleus in response to DNA damage) repair foci using a novel immunofluorescence method and correlate this with known molecular markers of breast cancer. Methods: Using primary tumors obtained from the ongoing PARPi clinical trials (NCT01017640 and NCT01251874) and tumor bank, we evaluated 102 breast tumors for the somatic functionality of the FA pathway (FANCD2 foci formation) by the FA Triple Stain Immuno-Fluorescence (FATSI) test performed in a CLIA-certified laboratory using paraffin embedded tissues. The tissue sections are incubated with a primary antibody cocktail of rabbit polyclonal FANCD2 antibody and a monoclonal anti-Ki67 mouse antibody, followed by co-incubation with a secondary antibody (FITC conjugated to anti-rabbit IgG and Alexafluor 594 donkey anti-mouse), mounted on glass slides in a DAPI containing embedding medium and evaluated by a fluorescence microscope. Absence of nuclear FANCD2 formation in 100 proliferating tumor cells was considered positive for FA defect. Hormone receptor (HR) and Her2 status was compared between the groups using Fisher's exact test. Results: A total of 102 primary breast tumors were analyzed for FANCD2 by FATSI test of which 62 were triple negative (TN), 37 were HR positive and 3 were Her2 positive. Of these, 29 tumors (28%) were positive for FA defect with no significant differences among the molecular subtypes (26% in TN vs 32% in HR + vs 33% in Her2+). Conclusions: We report a novel methodology to efficiently screen archival FFPE tumors for somatic functional defect of FA DNA repair pathway and demonstrated a high prevalence (one-third) in breast tumors irrespective of molecular subtype. We are currently conducting clinical trials with PARPi including patients with tumors that test positive for FA defect to demonstrate if such tumors are sensitive to PARPi. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD10-01.

The Fanconi anaemia pathway orchestrates incisions at sites of crosslinked DNA

Fanconi anaemia (FA) is a rare, autosomal recessive, genetically complex, DNA repair deficiency syndrome in man. Patients with FA exhibit a heterogeneous spectrum of clinical features. The most significant and consistent phenotypic characteristics are stem cell loss, causing progressive bone marrow failure and sterility, diverse developmental abnormalities and a profound predisposition to neoplasia. To date, 15 genes have been identified, biallelic disruption of any one of which results in this clinically defined syndrome. It is now apparent that all 15 gene products act in a common process to maintain genome stability. At the molecular level, a fundamental defect in DNA repair underlies this complex phenotype. Cells derived from FA patients spontaneously accumulate broken chromosomes and exhibit a marked sensitivity to DNA-damaging chemotherapeutic agents. Despite complementation analysis defining many components of the FA DNA repair pathway, no direct link to DNA metabolism was established until recently. First, it is now evident that the FA pathway is required to make incisions at the site of damaged DNA. Second, a specific component of the FA pathway has been identified that regulates nucleases previously implicated in DNA interstrand crosslink repair. Taken together, these data provide genetic and biochemical evidence that the FA pathway is a bona fide DNA repair pathway that directly mediates DNA repair transactions, thereby elucidating the specific molecular defect in human Fanconi anaemia.

Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma

The emergence of acquired drug resistance results from multiple compensatory mechanisms acting to prevent cell death. Simultaneous monitoring of proteins involved in drug resistance is a major challenge for both elucidation of the underlying biology and development of candidate biomarkers for assessment of personalized cancer therapy. Here, we have utilized an integrated analytical platform based on SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring mass spectrometry, a versatile and powerful tool for targeted quantification of proteins in complex matrices, to evaluate a well-characterized model system of melphalan resistance in multiple myeloma (MM). Quantitative assays were developed to measure protein expression related to signaling events and biological processes relevant to melphalan resistance in multiple myeloma, specifically: nuclear factor-κB subunits, members of the Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components. SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring methods were developed for quantification of these selected target proteins in amounts of material compatible with direct translation to clinical specimens (i.e. less than 50,000 cells). As proof of principle, both relative and absolute quantification were performed on cell line models of MM to compare protein expression before and after drug treatment in naïve cells and in drug resistant cells; these liquid chromatography-multiple reaction monitoring results are compared with existing literature and Western blots. The initial stage of a systems biology platform for examining drug resistance in MM has been implemented in cell line models and has been translated to MM cells isolated from a patient. The ultimate application of this platform could assist in clinical decision-making for individualized patient treatment. Although these specific assays have been developed to monitor MM, these techniques are expected to have broad applicability in cancer and other types of disease.

Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway.

Fanconi anemia is a cancer predisposition syndrome caused by defects in the repair of DNA interstrand cross-links (ICLs). Central to this pathway is the Fanconi anemia I-Fanconi anemia D2 (FANCI-FANCD2) (ID) complex, which is activated by DNA damage-induced phosphorylation and monoubiquitination. The 3.4 angstrom crystal structure of the ~300 kilodalton ID complex reveals that monoubiquitination and regulatory phosphorylation sites map to the I-D interface, suggesting that they occur on monomeric proteins or an opened-up complex and that they may serve to stabilize I-D heterodimerization. The 7.8 angstrom electron-density map of FANCI-DNA crystals and in vitro data show that each protein has binding sites for both single- and double-stranded DNA, suggesting that the ID complex recognizes DNA structures that result from the encounter of replication forks with an ICL.

Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2(-/-) embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2(+/-)) can support the development of double-mutant (Aldh2(-/-)Fancd2(-/-)) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2(-/-)Fancd2(-/-) mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.

Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2T

Background and purposeHypoxia is a common feature of the microenvironment of solid tumors which has been shown to promote malignancy and poor patient outcome through multiple mechanisms. The association of hypoxia with more aggressive disease may be due in part to recently identified links between hypoxia and genetic instability. For example, hypoxia has been demonstrated to impede DNA repair by down-regulating the homologous recombination protein RAD51. Here we investigated hypoxic regulation of UBE2T, a ubiquitin ligase required in the Fanconi anemia (FA) DNA repair pathway. Materials and methodsWe analysed UBE2T expression by microarray, quantitative PCR and western blot analysis in a panel of cancer cell lines as a function of oxygen concentration. The importance of this regulation was assessed by measuring cell survival in response to DNA damaging agents under normoxia or hypoxia. Finally, HIF dependency was determined using knockdown cell lines and RCC4 cells which constitutively express HIF1α. ResultsHypoxia results in rapid and potent reductions in mRNA levels of UBE2T in a panel of cancer cell lines. Reduced UBE2T mRNA expression is HIF independent and was not due to changes in mRNA or protein stability, but rather reflected reduced promoter activity. Exposure of tumor cells to hypoxia greatly increased their sensitivity to treatment with the interstrand crosslinking (ICL) agent mitomycin C. ConclusionsExposure to hypoxic conditions down-regulates UBE2T expression which correlates with an increased sensitivity to crosslinking agents consistent with a defective Fanconi anemia pathway. This pathway can potentially be exploited to target hypoxic cells in tumors.

Fanconi anaemia: from a monogenic disease to sporadic cancer

The dissection of the molecular pathways participating in genetic instability disorders has rendered invaluable information about the mechanisms of cancer pathogenesis and progression, and is offering a unique opportunity to establish targeted anticancer therapies. Fanconi anaemia (FA) is a paradigm of cancer-prone inherited monogenic disorders. Moreover, accumulated evidence indicates that genetic and epigenetic alterations in FA genes can also play an important role in sporadic cancer in the general population. Here, we summarise current progress in the understanding of the molecular biology of FA and review the principal mechanisms accounting for a disrupted FA pathway in sporadic cancer. Additionally, we discuss the impact of these findings in the development of new anticancer therapies, particularly with DNA interstrand crosslinkers and with new inhibitors of the FA and/or alternative DNA repair pathways.

Expanding the reach of Fanconi anaemia

Three papers report the involvement of SLX4 in the Fanconi anaemia DNA repair pathway, and two papers show that mutations in SLX4 cause a new subtype of Fanconi anaemia.