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Identifier 000423820
Title The functional role of nucleotide excision repair in transcription-associated DNA damage in mammals
Alternative Title Ο λειτουργικός ρόλος του μηχανισμού εκτομής νουκλεοτιδίων σε βλάβες του DNA που σχετίζονται με τη μεταγραφή στα θηλαστικά
Author Αγαθαγγέλου, Κυριάκος
Thesis advisor Γαρίνης, Γιώργος
Reviewer Σπηλιανάκης, Χαράλαμπος
Αλεξανδράκη, Δέσποινα
Τζαμαρίας, Δημήτρης
Δελιδάκης, Χρήστος
Ζάχος, Γιώργος
Κρετσόβαλη, Ανδρονίκη
Abstract DNA is not disposable or recyclable and must be repaired when damaged. All other cellular polymers, including RNA, proteins and polysaccharides, are regularly turned over, broken down and rebuilt based on the blueprint provided by the genetic information stored in DNA. Thus, as the maintenance of DNA integrity is vital to the proper functioning of every cell, so is DNA damage inexorably linked to cellular dysfunction. To meet this challenge, mammalian cells have evolved machineries to maintain telomeres intact as well as overlapping repair pathways to counteract structural DNA modifications (e.g., nicks, gaps, DNA double-strand breaks (DNA DSBs), and the myriad alterations that may block DNA transcription or replication). For bulky helix-distorting damage, such as the main Ultraviolet (UV)-induced lesions, the principal repair mechanism is the evolutionarily conserved Nucleotide Excision Repair (NER) pathway. In humans and the corresponding animal models, inborn mutations in genes involved in NER are associated with a wide range of clinical symptoms whose remarkable heterogeneity cannot be adequately explained by the random accumulation of DNA damage. Recent studies revealed that, in addition to DNA repair, NER factors are also involved in transcription initiation and elongation, chromatin remodeling and the 3D genome architecture. To dissect the functional role of NER during mammalian development and disease, we used an in vivo biotinylation-tagging approach and unbiased high-throughput genomics and proteomics approaches techniques in mice. Here, we show that the NER structure-specific endonuclease ERCC1-XPF complex interacts with protein factors involved in the resolution of DNA topological stress that is triggered during the process of transcription. Upon induction of mRNA synthesis, we find that the ERCC1-XPF complex recruits on promoters, genome-wide and that its recruitment on DNA coincides with the presence of DNA DSBs on these genomic regions. Together, our findings point to the involvement of ERCC1-XPF in the repair of transcription-associated DNA damage events, shedding new light into the pathological complications associated with NER-deficient syndromes.
Language English
Issue date 2021-07-28
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Doctoral theses
  Type of Work--Doctoral theses
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