Human POLD3 coordinates leading and lagging strand in Mitotic DNA Synthesis

Diplôme Thèse Human POLD3 coordinates leading and lagging strand in Mitotic DNA Synthesis eng 2023 2023 author Turati Demetrio 903580 director Halazonetis Thanos 641033 Département de biologie moléculaire et cellulaire (MOCEL) 10.13097/archive-ouverte/unige:174778 urn:nbn:ch:unige-1747789 Sc. Vie 242 <p>Deregulation of origin firing and licensing, shortage of deoxyribonucleotides in the cell and interference between transcription and replication are among the causes of DNA replication stress in cancer cells. This leads in various ways (notably, through common fragile sites expression and uncomplete replication of late replicating regions of the genome during S phase) to the necessity of finishing DNA replication in mitosis by a mechanisms called Mitotic DNA synthesis (MiDAS), which is related to Break Indu ced Replication (BIR). Even if it is of primary importance for cancer cells, the molecular mechanism of MiDAS, and generally of BIR, is not yet well understood. Recently, the third subunit of the eukaryotic DNA polymerase delta (POLD3) has been recognized as a key player of BIR, though its role is not yet clear. In this work, using a protocol established in our group to map at high resolution newly replicated DNA at MiDAS sites, we provide new insights into the molecular role of POLD3 in this repair me chani sm. In particular, by analy z ing MiDAS in mutant HeLa clones lacking the PCNA interacting domain of POLD3, we demonstrate that the interaction between POLD3 and PCNA is required for coordinating leading and lagging strand synthesis in MiDAS. This work represents an important step forward towards the comprehension of the molecular mechansisms of Mitotic DNA synthesis, the full understanding of which is of primary importance for the possible development of novel cancer therapies targeting BIR related pathways.</p> Dewey 570 7daed2ee-1311-4824-9df9-2e51260a966a Département de biologie moléculaire et cellulaire 16484 false 811 Groupe Halazonetis 307908b0-3938-41c6-887e-071cdbaaeda4 Thesis Restricted Thesis_Turati_Demetrio_with_imprima.pdf 5198822 application/pdf Private 2025-01-01 aa1a82b4a4d565b641b4d510e545ce541e718a23a83b7a0570cd976d3bbc93b4 1ffb944d-7cc5-4044-8f51-eeb01c83d17d Imprimatur Public file.pdf 319572 application/pdf 83fbc61144797b526d4c7071d02ab914cb693c8aa40a9fe8fb2e23890a4981c9 restrictedAccess Faculté des sciences / Section de biologie / Département de biologie moléculaire et cellulaire

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Human POLD3 coordinates leading and lagging strand in Mitotic DNA Synthesis				2023	319	1

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