Biology subjects

Serandour, A. A.

Publications and source records attributed to Serandour, A. A..

4 recordsLinked to original sources

bioRxiv2024

PARP inhibitor counteracts Temozolomide Resistance in Glioblastoma Multiforme

BackgroundGlioblastoma multiforme (GBM) is the most common malignant primary brain tumour in adults and is invariably associated with poor prognosis. Resistance to Temozolomide (TMZ), the standard chemotherapeutic agent, remains a major clinical challenge, particularly due to DNA mismatch repair (MMR) deficiencies. The aim of this study was to determine whether combining TMZ with the poly(ADP-ribose) polymerase inhibitor Olaparib (OLA) could overcome TMZ resistance in GBM. MethodsWe conducted in vitro experiments using U251 cell-line, including a TMZ-resistant derivative, and primary GBM cultures derived from patient tumours. A CRISPR/Cas9 knockout screen was employed to identify genes involved in TMZ resistance. Cell viability, proliferation, and morphology were assessed following treatment with TMZ, OLA, or their combination. ResultsThe CRISPR screen identified inactivation of MMR pathway genes as key mediators of TMZ resistance. Co-treatment with OLA and TMZ demonstrated synergistic cytotoxicity in both parental and TMZ-resistant U251 cells, as well as in primary GBM cultures at diagnosis or relapse. Notably, OLA restored sensitivity to TMZ in MMR-deficient contexts and in tumours expressing O6-methylguanine-DNA-methyltransferase (MGMT). The combination treatment induced persistent DNA damage, cell cycle disruption, and cell death. ConclusionsThese findings provide strong preclinical evidence that combining TMZ with OLA can effectively overcome key mechanisms of TMZ resistance in GBM. This approach offers a promising therapeutic strategy warranting further clinical investigation. IMPORTANCE OF THE STUDYTemozolomide (TMZ) resistance remains a major therapeutic obstacle in glioblastoma (GBM), often driven by MMR deficiency or MGMT expression. While poly(ADP-ribose) polymerase (PARP) inhibitors have shown potential in other cancers, their role in overcoming TMZ resistance in GBM has remained unclear. In this study, a CRISPR screen identified MMR deficiency as a key driver of TMZ resistance. We further demonstrate that co-treatment with the PARP inhibitor Olaparib (OLA) restores TMZ sensitivity in both MMR-deficient and MGMT-expressing GBM cells and patient-derived cultures. These findings provide strong preclinical evidence supporting PARP inhibition as a promising therapeutic strategy to overcome chemoresistance in GBM and justify further clinical investigation. KEY POINTSO_LIPARP inhibitor Olaparib restores temozolomide sensitivity in resistant GBM cells C_LIO_LICombination therapy overcomes resistance driven by MMR deficiency or MGMT expression C_LIO_LIDual treatment induces persistent DNA damage and apoptosis in glioblastoma primary cultures C_LI

cancer biology↗

bioRxiv2021

The neurodevelopmental disorder-linked PHF14 complex that forms biomolecular condensates detects DNA damage and promotes repair

Numerous chromatin-associated proteins have been linked to neurodevelopmental disorders, yet their molecular functions often remain elusive. PHF14, HMG20A, TCF20 and RAI1 are components of a putative chromatin-associated complex and have been implicated in neurological disorders. Here, we found that Phf14 knockout embryonic stem cells and neural progenitor cells exhibit impaired cell cycle progression and proliferation, inadequate protection of stalled replication forks, and decreased DNA repair. The PHF14 complex rapidly assembles at DNA damage sites and binds to DNA through HMG20A. The PHF14 complex forms DNA-containing phase separated droplets in vitro, where TCF20 facilitates droplet formation. Furthermore, TCF20 maintenance at DNA damage sites is destabilized upon pathological mutation. Our results suggest that the PHF14 complex contributes to DNA damage repair by sensing damaged sites and forming biomolecular condensates, thus supporting cell cycle progression, especially in neural progenitor cells whose spatiotemporal pool is critical for proper brain development.

molecular biology↗

bioRxiv2019

DNA hydroxymethylation reveals transcription regulation networks and prognostic signatures in multiple myeloma

Multiple myeloma (MM) is a plasma cell malignancy that remains challenging to cure despite a substantially improving median survival. During the last decade, DNA copy number variation and gene expression studies have described the pathology and its heterogeneity among patients. Epigenetic modifications play important roles in MM, but they are rarely associated with clinical aspects of the disease. In this epigenomics study, we produced quantifications of genomic 5-methylcytosine (5mC) and of 5-hydroxymethylcytosine (5hmC) as well as genome-wide maps of hydroxymethylation to analyse myeloma cells taken from a cohort of 40 newly diagnosed and homogeneously treated patients. We found 5hmC to be globally depleted in MM compared to normal plasma cells, as well as being reduced in advanced clinical stages of the disease. From the hydroxymethylome data, we observed that remaining 5hmC is organised in large peak clusters and is associated with well-known disease-related genes. Based on their signal correlation, these 5hmC peak clusters can be gathered in 2 regulation networks involving core transcription factors such as IRF4, MYC, PRDM1 and TCF3. By performing paired hydroxymethylomes at diagnosis and at relapse, we found the disease progression to be heterogeneous and patient-specific. We found that the location of 5hmC at tumor suppressor TP53INP1 is associated with better outcome while global high level of 5hmC tends to be associated with better overall survival. Together, our study suggests that 5hmC provides new biological insights of the disease severity and progression, and can be used for retrospective studies.\n\nKey PointsO_LI5hmC is globally depleted in MM and even more in advanced stages of the disease.\nC_LIO_LI5hmC is locally detected at transcriptionally active regions of MM where its presence can be associated with survival.\nC_LI

cancer biology↗

bioRxiv2018

A novel role for the HLH protein Inhibitor of Differentiation 4 (ID4) in the DNA damage response in basal-like breast cancer.

Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of Differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC, through unknown mechanisms. Here, we have defined a molecular mechanism of action for ID4 in BLBC and the related disease highgrade serous ovarian cancer (HGSOV), by combining RIME proteomic analysis and ChIP-Seq mapping of genomic binding sites. Remarkably, these studies have revealed novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins ({gamma}H2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage and regulating DNA damage signalling. Clinical analysis demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair pathways. These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOV.

cancer biology↗