“Telomeres offer a unique ambivalence between protection of the chromosomes against genome instability and a challenging sequence for fork progression during DNA replication.”
DNA replication is an essential process for genome duplication, cell division and ultimately organismal survival that ensures faithful transmission of the genome to progeny. Certain genomic loci represent major obstacles to DNA replication including fragile sites, G-rich tracts and repetitive sequences, such as rDNA and telomeres. Mammalian telomeres have the propensity to adopt complex DNA secondary structures, including telomere-loops and telomeric G-quadruplex, which are believed to play essential roles in telomere maintenance. However, recent work has established that these structures are also a hindrance to DNA replication and might represent a potential source of genome instability, the hallmark of many diseases including cancer.
What is the nature of telomere fragility?
Despite recent advances, the mechanisms that facilitate DNA replication at mammalian telomeres remain unclear. It is important to address this question to decipher the mechanisms that help DNA replication through DNA secondary structures. Our group uses multidisciplinary approaches to investigate the cellular response to replication stress and the enzymatic activities that result in telomere replication aberrations, which involves direct visualisation of telomere abnormalities using complementary DNA-related methodologies and analysis of novel telomere-associated complexes. It is also critical to understand the structure of fragile telomeres, which remains poorly defined and represent a central question for the field using visualisation of biological molecules and proteomics.
The detailed investigation of the function of known and new factors that facilitate telomere DNA replication represent an outstanding challenge that will provide a novel framework for understanding the contributions of replication factors in general DNA replication, genome stability and cancer.
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