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12th EDRA webinar, June 25th 2024 - 4:00pm12th EDRA Webinar June 25th, 2024, from 4:00 to 5:30 pm (CET)
Dr. Anna Campalans - Keynote speaker Institute of Cellular and Molecular Radiobiology - François Jacob - CEA, Fontenay-aux Roses, France Repair of oxidative DNA damage in the chromatin context Oxidative stress induces a plethora of DNA lesions, among which 8-oxoguanine (8-oxoG), a product of guanine oxidation, is the most abundant one. 8-oxoG is a highly mutagenic lesion that is repaired by the Base excision repair (BER) pathway, initiated by the recognition and excision of the modified base by the DNA glycosylase OGG1. Finding 8-oxoG in the context of nuclear architecture in which the DNA is highly compacted in chromatin is a challenging task for OGG1. Yet, the timely restoration of genome integrity is essential since inefficient clearance of oxidative lesions has been associated to multiple pathologies, including cancers as well as neurodegenerative diseases. I will present our recent discoveries concerning OGG1 dynamics in the chromatin context and discuss the potential use of OGG1 inhibitors as new promising therapeutic tools.
Dr. Tanveer Ahmad - Short talk Institute for Advanced Biosciences, IAB, La Tronche, France Dynamics of RNF113A methylation and its role in SCLC sensitivity to alkylation damage Small cell lung cancer (SCLC) represents the most lethal form of lung cancer, with poor survival due in part to chemoresistance towards limited available therapeutic agents. Lysine methyltransferase SMYD3 is upregulated in SCLC. We have previously established SMYD3 as a critical regulator of SCLC sensitivity towards alkylation-based chemotherapy. SMYD3 mediated methylation of RNF113A obstructs its interaction with phosphatase PP4 and governs its phosphorylation levels. This well coordinated dialogue between posttranslational modifications plays a crucial role to endorse and preserve the E3 ligase activity of RNF113A which is essential for its function in alkylation DNA damage response. Active form of RNF113A methylated by SMYD3 leads to better activation of the ASCC damage repair pathway and promotes cellular resistance to alkylation damage. Remarkably, SMYD3 inhibition revives the sensitivity of SCLC cells to alkylating drugs and promotes sustained response to chemotherapy.
Dr. Ana Boavida - Short talk Istituto di Biochimica e Biologia Cellulare (IBBC) – CNR, Naples, Italy FANCJ, the missing piece of AND-1 interaction hub at the DNA replication fork FANCJ, a DNA helicase linked to Fanconi anemia and frequently mutated in cancers, counteracts replication stress by dismantling unconventional DNA secondary structures (such as G-quadruplexes) that occur at the DNA replication fork in certain sequence contexts. However, how FANCJ is recruited to the replisome is unknown. Here, we report that FANCJ directly binds to AND-1 (the vertebrate ortholog of budding yeast Ctf4), a homo-trimeric protein adaptor that connects the CDC45/MCM2-7/GINS replicative DNA helicase with DNA polymerase α and several other factors at DNA replication forks. The interaction between FANCJ and AND-1 requires the integrity of an evolutionarily conserved Ctf4-interacting protein (CIP) box located between the FANCJ helicase motifs IV and V. Disruption of the CIP box significantly reduces FANCJ association with the replisome, causing enhanced DNA damage, decreased replication fork recovery and fork asymmetry in cells unchallenged or treated with Pyridostatin, a G-quadruplex-binder, or Mitomycin C, a DNA inter-strand cross-linking agent. Cancer-relevant FANCJ CIP box variants display reduced AND-1-binding and enhanced DNA damage, a finding that suggests their potential role in cancer predisposition. |
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