The team, lead by P. Kannouche, comprises three different research groups (Kannouche, Aoufouchi and Rosselli) adressing complementary questions on genome plasticity, mutagenesis and DNA damage tolerance pathways, notably translesion synthesis.
Translesion Synthesis (TLS): A Compromise Between Limited Mutagenesis and Chromosomal Instability (Kannouche Group)
Natural barriers or DNA damage can cause replicative polymerases to stall, leading to replication fork blockages, halting cell cycle progression, and activating intra-S phase checkpoints. A failure to restart these stalled forks can have serious consequences, as they may potentially lead to double-strand breaks and cause chromosomal instability, which is closely linked to tumorigenesis. Therefore, cells have developed DNA damage tolerance strategies that allow the replication machinery to bypass DNA lesions that block forks. One of the major mechanisms is translesion synthesis (TLS), which involves specialized low-fidelity DNA polymerases that, unlike replicative DNA polymerases, can replicate damaged DNA—albeit in an error-prone manner. Consequently, the TLS process plays a « paradoxical » role in maintaining genome stability: while it is responsible for a large proportion of point mutations in the genome, it also prevents more severe mutational events, such as chromosomal rearrangements.
The various roles of TLS polymerases highlight the need to understand how these specialized enzymes are regulated and connected with DNA replication, repair, epigenetic maintenance, and chromatin architecture in mammalian cells. Gaining insight into these processes is essential for advancing new concepts in cancer development and treatment.
Stimulating Mutagenesis: Somatic Hypermutation During Immunoglobulin Diversification (Aoufouchi Group)
In addition to their role in replicating damaged DNA, translesion DNA polymerases have been co-opted into a number of other related processes. During the development of the immune response, the immunoglobulin genes of vertebrates undergo a particularly high rate of targeted mutagenesis, known as Somatic Hypermutation, induced by the protein AID (activation-induced deaminase). Although AID can only deaminate dC to dU, its action leads to mutations on all four bases through a series of reactions that heavily depend on translesion DNA polymerases.
The dU formed by AID action is removed by uracil DNA glycosylase (UNG), resulting in an abasic site. Direct replication over this abasic site involves the TLS polymerase REV1 and generates mutations at dG-dC base pairs. Recognition of dU can also lead to the formation of a single-stranded gap, and its filling primarily involves the TLS polymerase eta (polη), which generates mutations at dA-dT base pairs.
Multifaceted Roles of FANC Proteins in Genome & Cellular Integrity (Rosselli Group)
Our research focuses on the impact of FANC proteins (Fanconi Anemia-associated gene products) from DNA damage responses to gene expression and protein synthesis.
We made significant advances in understanding Fanconi anemia, revealing that FANCA plays key roles beyond DNA damage response, including maintaining nucleolar homeostasis, ribosome biogenesis, and protein synthesis. We have also uncovered how loss of FANCA function affects cell differentiation and contributes to leukemic transformation. Building on these findings, we continue to explore the diverse cellular functions of FANC proteins.
