Fanconi anaemia (FA) is the most frequent inherited bone marrow failure syndrome, due to mutations in genes encoding proteins involved in replication fork protection, DNA interstrand crosslink repair and replication rescue through inducing double-strand break repair and homologous recombination. Clinically, FA is characterised by aplastic anaemia, congenital defects and cancer predisposition. In in vitro studies, FA cells presented hallmarks defining senescent cells, including p53-p21 axis activation, altered telomere length, mitochondrial dysfunction, chromatin alterations, and a pro-inflammatory status. Senescence is a programme leading to proliferation arrest that is involved in different physiological contexts, such as embryogenesis, tissue remodelling and repair and guarantees tumour suppression activity. However, senescence can become a driving force for developmental abnormalities, aging and cancer. Herein, we summarise the current knowledge in the field to highlight the mutual relationships between FA and senescence that lead us to consider FA not only as a DNA repair and chromosome fragility syndrome but also as a “senescence syndrome”.

Fanconi Anemia (FA), due to the loss-of-function of the proteins that constitute the FANC pathway involved in DNA replication and genetic stability maintainance, is a rare genetic disease featuring bone marrow failure, developmental abnormalities and cancer predisposition. Similar clinical stigmas have also been associated with alterations in the senescence program, which is activated in physiological or stress situations, including the unscheduled, chronic, activation of an oncogene (oncogene induced senescence, OIS). Here, we wanted to determine the crosstalk, if any, between the FANC pathway and the OIS process. OIS was analyzed in two known cellular models, IMR90-hTERT/ER:RAS^G12V and WI38-hTERT/ER:GFP:RAF1, harboring 4-hydroxytamoxifen-inducible oncogenes. We observed that oncogene activation induces a transitory increase of both FANCA and FANCD2 as well as FANCD2 monoubiquitination, readout of FANC pathway activation, followed by their degradation. FANCD2 depletion, which leads to a pre-senescent phenotype, anticipates OIS progression. Coherently, FANCD2 overexpression or inhibition of its proteosomal-dependent degradation slightly delays OIS progression. The pro-senescence protease cathepsin L, which activation is anticipated during OIS in FANCD2-depleted cells, also participates to FANCD2 degradation. Our results demonstrate that oncogene activation is first associated with FANCD2 induction and activation, which may support initial cell proliferation, followed by its degradation/downregulation when OIS proceeds.

The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient’s cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function.

Fanconi Anemia (FA) is a rare inherited recessive disorder characterized by bone marrow failure, congenital abnormalities, and a predisposition to myeloid leukemia and some solid cancers. FA is caused by mutations in one of the 22 so-called FANC genes, with two thirds of FA patients being FANCA mutants. FANC proteins cooperate within the FANC/BRCA pathway, a DNA repair system essential for resolving DNA interstrand crosslinks (ICLs) in S-phase. The canonical understanding of FA pathogenesis involves genome instability and impaired cellular proliferation due to DNA damage accumulation and stress response overactivation. However, recent data shows FANCA has a function in ribosome biogenesis and translation, which prompts a reassessment of FANCA’s role(s) in cellular physiology and FA pathogenesis. We reasoned that unveiling the multiple interactions of the FANCA protein would shed light on these potentially new FANCA functions. By combining immunoprecipitation and BioID approaches, in three different cell lines and with different in silico analysis methods, we constructed lists of FANCA interactome proteins of different levels of selectivity and assembled them into a novel multilayered FANCA protein-protein interaction (PPI) landscape. Strikingly, we find that FANCA associates with proteins involved in processes distinct from DNA repair, such as translation, ribosome biogenesis, mRNA splicing, nucleocytoplasmic transport, chromatin remodeling, and the TCA cycle. We then analyzed the protein content of polysome profiling fractions and found that FANCA loss may affect ribosomal protein stoichiometry within ribosomal subunits. Overall, our data expands FANCA’s PPI network far beyond the previously reported interactions. Importantly, we confirm the biological significance of low-selectivity interactions and propose to re-evaluate their importance in proteomic studies. The study of previously unsuspected FANCA functions, such as translation, could provide new therapeutic targets in FA and therefore improve patient care.