Biology subjects

Foucher, A.-E.

Publications and source records attributed to Foucher, A.-E..

3 recordsLinked to original sources

bioRxiv2026

KDM7B-mediated demethylation of RNF113A regulates small cell lung cancer sensitivity to alkylation damage

Chemoresistance remains a major obstacle to effective cancer treatment, often driven by enhanced DNA repair mechanisms that enable tumor cells to withstand genotoxic therapies. One such pathway involves the atypical DNA damage repair complex ALKBH3-ASCC, activated by the E3 ligase RNF113A in response to alkylation damage. We previously showed that SMYD3-dependent methylation of RNF113A stimulates this pathway, enhancing DNA repair and promoting resistance. Here, we identify KDM7B/PHF8 as the bona fide RNF113A demethylase, establishing one of the first functional examples of a dynamic, reversible non-histone methylation event regulating genome integrity. KDM7B antagonizes SMYD3 activity by maintaining low levels of methylated RNF113A, thereby limiting ASCC activation and sensitizing cancer cells to alkylating agents. To dissect this regulation in depth, we focused on small cell lung cancer (SCLC), a particularly aggressive malignancy characterized by limited therapeutic options and rapid acquisition of resistance. In SCLC, high KDM7B levels correlate with improved patient prognosis, whereas xenografts with reduced expression exhibit diminished responses to alkylating treatment. Moreover, CRISPR-based on/off modulation of KDM7B in genetically engineered SCLC mouse models demonstrates its central role in determining tumor response to chemotherapy. Our findings position the RNF113A-ASCC axis as a central modulator of chemoresistance, regulated through a post-translational methylation switch representing an innovative therapeutic vulnerability that could be exploited to enhance the efficacy of alkylating agents. Targeting this pathway may provide new opportunities to overcome chemoresistance, with KDM7B levels serving as a predictive biomarker to guide treatment in SCLC.

cell biology↗

bioRxiv2023

Structural basis for competitive binding of productive and degradative co-transcriptional effectors to the nuclear cap-binding complex

The nuclear cap-binding complex (CBC) co-ordinates co-transcriptional maturation, transport, or degradation of nascent Pol II transcripts. CBC with its partner ARS2 form mutually exclusive complexes with diverse effectors that promote either productive or destructive outcomes. Combining Alphafold predictions with structural and biochemical validation, we show how effectors NCBP3, NELF-E, ARS2, PHAX and ZC3H18 form competing binary complexes with CBC and how PHAX, NCBP3, ZC3H18 and other effectors compete for binding to ARS2. In ternary CBCA complexes with either PHAX, NCBP3 or ZC3H18, ARS2 is responsible for the initial effector recruitment but inhibits their direct binding to the CBC. We show that in vivo ZC3H18 binding to both CBC and ARS2 is required for nuclear RNA degradation. We propose that recruitment of PHAX to CBC-ARS2 can lead, with appropriate cues, to competitive displacement of ARS2 and ZC3H18 from the CBC, thus promoting a productive rather than a degradative RNA fate.

biochemistry↗

bioRxiv2022

Structural analysis of Red1 as a conserved scaffold of the RNA-targeting MTREC/PAXT complex

To eliminate specific or aberrant transcripts, eukaryotic cells use nuclear RNA-targeting complexes that deliver them to the exosome for degradation. S. pombe MTREC complex, and its human counterpart PAXT, are key players in this mechanism. Red1 and hZFC3H1 function as scaffolds of these respective complexes. Here, we present an NMR structure of a helix-turn-helix domain of Red1 in complex with the N-terminus of Iss10 and show this interaction is required for proper cellular growth and meiotic mRNA degradation. We also report a crystal structure of a Red1-Ars2 complex that explains the mutually exclusive interactions of hARS2 with various "ED/EGEI/L" motif-possessing RNA regulators such as hZFC3H1, hFLASH or hNCBP3. Finally, we show that both Red1 and hZFC3H1 homo-dimerize via their coiled-coil regions indicating that MTREC and PAXT likely function as dimers. Our results, combining structures of three Red1 binding interfaces with in vivo studies, provide mechanistic insights into conserved features of MTREC/PAXT architecture.

biochemistry↗