Biology subjects

Badja, C.

Publications and source records attributed to Badja, C..

5 recordsLinked to original sources

bioRxiv2026

Global signatures of Ribonucleotide Excision Repair deficiency and its therapeutic vulnerabilities

Cancer therapies increasingly exploit DNA repair deficiencies, yet many clinically actionable repair-deficient states remain undetectable because they lack robust biomarkers and are not identifiable through gene-based diagnostics. Here, we show that deficiency of ribonucleotide excision repair (RER), a pathway that removes misincorporated ribonucleotides from genomic DNA, generates a distinct genome-wide mutational phenotype comprising characteristic insertion-deletion, substitution, and structural variation signatures. Using these features, we developed RERDetect, a whole-genome classifier that identifies RER-deficient tumors across diverse cancer types. Application of RERDetect to more than 11,000 primary and metastatic cancers revealed a recurrent subset of tumors with evidence of RER deficiency, the majority lacking detectable genetic alterations in RNASEH2 genes. We identified promoter hypermethylation of RNASEH2C as a recurrent mechanism of pathway inactivation. RER-deficient cells exhibited distinct vulnerabilities, including sensitivity to EXO1 and FANCM inhibition. These findings establish RER deficiency as a previously unrecognized and therapeutically actionable DNA repair-deficient state in cancer, demonstrating the power of mutational scars to identify clinically relevant tumor phenotypes that evade conventional genomic diagnostics.

genomics↗

bioRxiv2026

BCOR mutations establish a persistent culture-adaptive state in human induced pluripotent stem cells

Human induced pluripotent stem cells (hiPSCs) are widely used for disease modelling and regenerative medicine, yet their utility depends on maintaining molecular integrity during long-term culture. BCOR (BCL6 Co-Repressor) mutations are among the most recurrent culture-acquired alterations in hiPSCs, but their functional consequences remain poorly understood. Here, we show that hiPSC BCOR mutations are predominantly truncating indels enriched in exon 7, defining a mutational landscape distinct from that observed in cancer. Multi-omics profiling reveals that BCOR loss drives widespread chromatin, transcriptomic and proteomic remodelling, with coordinated activation of developmental, pluripotency-associated and mitochondrial metabolism programmes. To facilitate routine surveillance, we develop a cost-effective TaqMan qPCR assay that accurately identifies BCOR-mutant hiPSCs across independent cell lines. Finally, we demonstrate that correction of BCOR mutation by CRISPR-Cas9 only partially restores the wildtype molecular state, highlighting the importance of early detection and monitoring of adaptive mutations in hiPSC cultures.

cell biology↗

bioRxiv2026

Mutational and functional heterogeneity of homology-directed repair deficiency and clinical implications

Homology-directed repair deficiency (HRd) encompasses mutations in multiple genes yet is treated clinically as a single entity. Here, through parallel analyses of isogenic knockouts of multiple HR pathway genes, integrating multi-omic analyses with genome-wide CRISPR-Cas9-dependency and resistance screens, we show that HRd is not a single entity but exists along a molecular and functional continuum. BRCA1, BRCA2, PALB2, RAD51C, and RAD51D mutants shared many HRd-associated mutational signatures, while RAD51B, BRIP1, CDK12 exhibited distinct genomic patterns. Functional heterogeneity was equally apparent: synthetic lethal interactions including CIP2A and a novel dependency on PRDX1 were penetrant across most HRd genotypes, whereas FANCM dependency was linked to HRd subtypes characterized by tandem duplications. PARPi resistance screens in distinct HRd contexts uncovered BRIP1 and RECQL5 as new BRCA2-specific resistance genes. HRd is thus a complex continuum, underscoring why modernizing the molecular taxonomy utilizing all genomic features available per patient is crucial to informing precision interventions.

genomics↗

bioRxiv2020

Dissecting mutational mechanisms underpinning signatures caused by replication errors and endogenous DNA damage

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. Here, we generate isogenic CRISPR-Cas9 knockouts ({Delta}) of 43 genes in human induced pluripotent stem cells, culture them in the absence of added DNA damage, and perform wholegenome sequencing of 173 daughter subclones. {Delta}OGG1, {Delta}UNG, {Delta}EXO1, {Delta}RNF168, {Delta}MLH1, {Delta}MSH2, {Delta}MSH6, {Delta}PMS1, and {Delta}PMS2 produce marked mutational signatures indicative of being critical mitigators of endogenous DNA changes. Detailed analyses reveal that 8-oxo-dG removal by different repair proteins is sequence-context-specific while uracil clearance is sequencecontext-independent. Signatures of mismatch repair (MMR) deficiency show components of C>A transversions due to oxidative damage, T>C and C>T transitions due to differential misincorporation by replicative polymerases, and T>A transversions for which we propose a reverse template slippage model. {Delta}MLH1, {Delta}MSH6, and {Delta}MSH2 signatures are similar to each other but distinct from {Delta}PMS2. We validate these gene-specificities in cells from patients with Constitutive Mismatch Repair Deficiency Syndrome. Based on these experimental insights, we develop a classifier, MMRDetect, for improved clinical detection of MMR-deficient tumors.

genomics↗

bioRxiv2018

Analysis of the 4q35 chromatin organization reveals distinct long-range interactions in patients affected with Facio-Scapulo-Humeral Dystrophy.

Facio-Scapulo Humeral dystrophy (FSHD) is the third most common myopathy, affecting 1 amongst 10,000 individuals (FSHD1, OMIM #158900). This autosomal dominant pathology is associated in 95% of cases with genetic and epigenetic alterations in the subtelomeric region at the extremity of the long arm of chromosome 4 (q arm). A large proportion of the remaining 5% of cases carry a mutation in the SMCHD1 gene (FSHD2, OMIM #158901). Here, we explored the 3D organization of the 4q35 locus by three-dimensions DNA in situ fluorescent hybridization (3D-FISH) in primary cells isolated from patients. We found that D4Z4 contractions and/or SMCHD1 mutations impact the spatial organization of the 4q35 region and trigger changes in the expression of different genes. Changes in gene expression was corroborated in muscle biopsies suggesting that long distance interaction modulate expression of a number of genes at the 4q35 locus in FSHD. Using induced pluripotent stem cells (hIPSC), we examined if chromatin organization is inherited or acquired during differentiation. Our data suggest that folding of the 4q35 region is modified upon differentiation. These results together with previous findings highlight the role of the D4Z4 repeat in the organization of chromatin and further indicate that the D4Z4-dependent 3D structure induces transcriptional changes of 4q35 genes expression.

cell biology↗