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Genomic signature of Fanconi anemia DNA repair pathway deficiency in cancer

ABSTRACT: Fanconi anemia (FA), a model syndrome of genome instability, is caused by a deficiency in DNA interstrand crosslink (ICL) repair resulting in chromosome breakage. The FA repair pathway protects against carcinogenic endogenous and exogenous aldehydes. Individuals with FA are hundreds to thousands-fold more likely to develop head and neck (HNSCC), esophageal and anogenital squamous cell carcinomas (SCCs). Molecular studies of SCCs from individuals with FA (FA SCCs) are limited, and it is unclear how FA SCCs relate to sporadic HNSCCs primarily driven by tobacco and alcohol exposure or human papillomavirus (HPV) infection. Here, by sequencing FA SCCs, we demonstrate that the primary genomic signature of FA-deficiency is the presence of high numbers of structural variants (SVs). SVs are enriched for small deletions, unbalanced translocations, and fold-back inversions, and are often connected, thereby forming complex rearrangements. They arise in the context of TP53 loss, but not HPV infection, and lead to somatic copy number alterations of HNSCC driver genes. We further show that FA pathway deficiency may lead to epithelial-to-mesenchymal transition and enhanced keratinocyte intrinsic inflammatory signaling, which would contribute to the aggressive nature of FA SCCs. We propose that genomic instability in sporadic HPV-negative HNSCC may arise consequent to the FA repair pathway being overwhelmed by ICL damage caused by alcohol and tobacco-derived aldehydes, making FA SCC a powerful model to study tumorigenesis resulting from DNA crosslinking damage.

ORGANISM(S): Mus musculus

PROVIDER: GSE195811 | GEO | 2022/09/04

REPOSITORIES: GEO

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Interactome analysis of elongating RNAPII after induction of DNA damage by IP-MS/MS

Project description:Endogenous aldehydes induce inter-strand crosslinks (ICL) and DNA-protein crosslinks (DPC). While DNA-repair and aldehyde-clearance systems cope with cellular toxicity, deficiencies in these mechanisms cause genome-instability disorders. The FA-pathway, defective in Fanconi anemia (FA), specifically removes ICL. In contrast, SPRTN, compromised in Ruijs-Aalfs syndrome, eliminates DPC during replication. However, AMeDS patients lacking aldehyde-detoxification display combined features of FA and Cockayne syndrome, associated with transcription-coupled repair (TCR) deficiency, suggesting a novel repair mechanism for aldehyde-induced DNA lesions in active genes. In this report, we demonstrate efficient resolution of aldehyde-induced transcription-blocking lesions by TCR. Mass-spectrometry and DPC-seq identify the TCR complex and additional factors involved in DPC removal and formaldehyde-induced damage tolerance. Notably, TFIIS-dependent cleavage of stalled-RNAPII transcripts exclusively protects against formaldehyde-induced damage. A mouse-model lacking both aldehyde-clearance and TCR pathways confirms endogenous DPC accumulation in transcribed regions. These findings highlight the importance of DPC removal in preventing transcription-roadblocks and contribute to understanding disorders related to aldehyde clearance and TCR deficiencies.

2024-02-12 | PXD044310 | Pride

Cooperation of the NEIL3 and Fanconi Anemia/BRCA Pathways in Interstrand Crosslink Repair

Project description:The NEIL3 DNA glycosylase is a base excision repair enzyme that excises bulky base lesions from DNA. Although NEIL3 has been shown to unhook interstrand crosslinks (ICL) in Xenopus extracts, how NEIL3 participants in ICL repair in human cells and its corporation with the canonical Fanconi anemia (FA)/BRCA pathway remain unclear. Here we show that the NEIL3 and the FA/BRCA pathways are non-epistatic in psoralen-ICL repair. The NEIL3 pathway is the major pathway for repairing psoralen-ICL, and the FA/BRCA pathway is only activated when NEIL3 is not present. Mechanistically, NEIL3 is recruited to psoralen-ICL in a rapid, PARP-dependent manner. Importantly, the NEIL3 pathway repairs psoralen-ICLs without generating double-strand breaks (DSBs), unlike the FA/BRCA pathway. In addition, we found that the RUVBL1/2 complex physically interact with NEIL3 and function within the NEIL3 pathway in psoralen-ICL repair. Moreover, TRAIP is important for the recruitment of NEIL3 but not FANCD2, and knockdown of TRAIP promotes FA/BRCA pathway activation. Interestingly, TRAIP is non-epistatic with both NEIL3 and FA pathways in psoralen-ICL repair, suggesting that TRAIP may function upstream of the two pathways. Taken together, the NEIL3 pathway is the major pathway to repair psoralen-ICL through a unique DSB-free mechanism in human cells.

2020-01-20 | PXD016256 | Pride

Human HEK293T cells LC-MS/MS (Gel-based proteomics)

Project description:Fanconi Anemia (FA) pathway is essential for the repair of inter-strand crosslink (ICLs). ICL induces stalled replication forks and triggers activation of FA pathway for efficient ICL repair. Given that stalled replication fork is proximal to ICLs sites, fork-associated proteins may likely coordinate with FA factors to rapidly sense ICLs for activation of FA signaling. We will use LC-MS/MS to identify such proteins that participated in the ICL repairs.

2023-05-10 | PXD028246 | Pride

SCAI orchestrates DNA interstrand crosslink repair downstream of FANCI-FANCD2 ubiquitylation

Project description:By covalently linking Watson and Crick strands, DNA interstrand crosslinks (ICLs) are highly toxic lesions that block DNA replication and threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI-FANCD2 (ID2) marking the activation step that triggers incisions on one DNA strand to unhook the ICL. ICL unhooking generates a two-ended double-strand break (DSB) on one of the daughter molecules, while leaving a gap comprising the ICL-adduct on the other. Restoration of the adducted molecule by DNA polymerase zeta-mediated translesion synthesis (TLS) creates a template required for repair of the DSB via homologous recombination (HR), but how these processes are coordinated to ensure faithful ICL repair is not known. Here, we uncover a crucial role for SCAI in promoting ICL repair downstream of ID2 activation. Using Xenopus egg extracts and human cells, we show that SCAI forms a complex with DNA polymerase zeta and localizes to ICLs during DNA replication. SCAI-deficient cells are exquisitely sensitive to ICL-inducing drugs and display principal hallmarks of FA gene inactivation, including broken and radial chromosome accumulation. In the absence of SCAI, DSB intermediates are preferentially re-ligated by illegitimate DNA polymerase theta-dependent microhomology-mediated end-joining (MMEJ). Consistently, the hypersensitivity of SCAI-deficient cells to ICLs can be reverted by suppressing FA pathway activation. Our work establishes SCAI as a critical mediator of ICL resolution via the FA pathway, acting at the interphase of the TLS and HR steps to prevent erroneous repair and chromosomal instability.

2022-02-18 | PXD024280 | Pride

SCAI orchestrates DNA interstrand crosslink repair downstream of FANCI-FANCD2 ubiquitylation (total proteome)

2022-02-18 | PXD029409 | Pride

RBBP9 interactors in Fanconi Anaemia

Project description:The Fanconi Anaemia (FA) pathway resolves replication fork-stalling inter-strand crosslinks (ICLs) and is mutated in Fanconi anaemia. FA is a rare recessive chromosomal instability syndrome, resulting in hypersensitivity to DNA-crosslinkers, and particularly disadvantageous for stem cell growth and maintenance. FA individuals have an increased risk to haematological malignancies (AML) and head-and-neck squamous cell carcinomas (HNSCC), often very aggressive. Systemic intolerance due to somatic cell hypersensitivity to standard chemo-radio-therapy in patients limits treatment options in FA-HNSCC underscoring an urgent, unmet need to develop novel therapeutic strategies. Here, we performed unbiased functional genomic siRNA screens to unveil genetic interactions that are synthetic lethal with FA pathway deficiency, in a panel of patient-derived, FA-core-complex mutated HNSCC cell lines. We identified RBBP9, LAMTOR2, PSMB2 and PSMC1, among others, as potential FA-HNSCC-specific hits. We demonstrate that RBBP9, a poorly characterized serine hydrolase is synthetically lethal in FA-defective HNSCC and crucial for FA-HNSCC survival. RBBP9 interaction partners are identified in a RBBP9-FLAG IP-MS experiment.

2022-10-27 | PXD026545 | Pride

miRNA expression in head and neck squamous cell carcinoma (HNSCC)

Project description:The involvement of microRNAs (miRNAs) in cancer and their potential as biomarkers of diagnosis, prognosis and response to therapy is becoming increasingly appreciated. The etiology of head and neck squamous cell carcinoma (HNSCC) is predominantly associated with the synergistic effects of tobacco and alcohol use, as well as Human Papilloma Virus (HPV) infection, which embodies a distinct clinical and biological phenotype. We sought to examine whether the profile of miRNAs in HNSCC varies based on HPV status, and to identify specific miRNAs altered in head and neck carcinogenesis. Total RNA was isolated from 16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines. The miRNA profile of 662 individual miRNAs in these tissues was examined by microarray. 18 miRNAs are significantly altered in their expression between normal tissues and HNSCC tumors and 5 miRNAs are identified as significantly differentially expressed between HPV-positive (HPV+) and HPV-negative (HPV-) tumors. A striking difference in expression pattern of miRNA was also observed between primary tissues and cell lines. These data suggest that the pattern of miRNA expression may be reflective of disease etiology, and may be useful in the realm of diagnostic biomarkers defining broadly responsive prevention and treatment strategies for HNSCC. These data also suggest that cultured tumor cell lines may be inappropriate for novel miRNA biomarker identification. Keywords: miRNA; Disease-state analysis Expression of 662 individual miRNA was assessed in16 HNSCC fresh frozen primary tumors, 5 fresh frozen non-diseased head and neck epithelial tissues, and 2 HNSCC cell lines were arrayed

2010-05-19 | E-GEOD-11163 | biostudies-arrayexpress

miRNA expression in head and neck squamous cell carcinoma (HNSCC)

2008-09-30 | GSE11163 | GEO

Gene expression profiling of African American vs European American HPV-negative oropharyngeal squamous cell carcinomas

Project description:Head and neck cancer (HNC) is the fifth most common malignancy worldwide with an annual mortality rate of 200,000. About 90% of HNC can be classified as head and neck squamous cell carcinomas (HNSCC), of which approximately 75% are attributed to alcohol and tobacco consumption and 25% are associated with human papillomavirus (HPV), predominantly HPV16. HPV-associated OPC have better prognosis and a more favorable response to therapy as compared to HPV-negative tumors. Differences in risk factors, age of presentation, clinical behavior and gene expression profiles indicate that HPV-positive and HPV-negative tumors develop via different molecular mechanisms and are biologically distinct. African American (AA) males have a higher incidence of HNC than any other racial/gender group, and a mortality rate almost three-fold that observed in European American (EA) males. Overall, AA patients tend to present with more HPV-negative OPC and have worse prognosis as compared to both HPV-positive and HPV-negative HNSCC in EA patients. Despite the unveiling of differential gene expression patterns, genetic and epigenetic profiles and the compilation of a mutational landscape along with preliminary TCGA data of HPV-related and unrelated HNC, the molecular determinants of the racial disparity in HNC are yet to be identified. This study aimed to compare the gene expression profiles of HPV-negative HNSCC from AA and EA patients, and determine their biological differences. ANALYSIS 2: Two-condition, on-color experiment: African American (AA) vs European American (EA) HPV-negative oropharyngeal squamous cell carcinomas. Biological replicates: 8 African American and 8 European American.

2014-03-05 | E-GEOD-55543 | biostudies-arrayexpress

Gene expression profiling of African American vs European American HPV-negative oropharyngeal squamous cell carcinomas

2014-03-05 | GSE55543 | GEO

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