Genome integrity, immune response and cancer
This team belongs to the UMR 9019 Genome Integrity and Cancers.
Translesion synthesis Process: a trade-off between limited mutagenesis and chromosomal instability
Bulky lesions or natural barriers in the DNA can cause arrest of replicative polymerases, halting cell cycle progression and activating DNA damage checkpoints. Failure to relieve such DNA replication stress can have dire consequences for the cell, as stalled replication forks are prone to collapse and could potentially lead to double-strand breaks (DSBs) that result to gross chromosomal instability that have a close link to tumourigenesis. Thus, cells have evolved DNA damage tolerance strategies enabling the replication machinery to bypass fork-blocking lesions. The major DNA damage bypass mechanism in mammalian cells entails specialised low-fidelity translesion DNA synthesis (TLS) polymerases, which unlike replicative DNA polymerases can replicate damaged DNA, albeit in an error-prone manner. Therefore TLS has a conflicting role in genome stability maintenance, as it accounts for a large proportion of DNA damage-induced mutagenesis but prevents even more severe forms of genome instability such as chromosome rearrangements.
Boosting the mutagenesis: Somatic hypermutation during Immunoglobulin diversification
In addition to their roles in the replication of damaged DNA, TLS polymerases have been co-opted into a number of other related processes. During development of the immune response, the antibody genes of vertebrates exhibit a particularly high rate of focused mutagenesis, known as somatic hypermutation, which is driven by activation-induced deaminase (AID). Although AID can only deaminate dC to dU, its action gives rise to mutations at all four bases in a series of reactions that crucially depend on the Y-family polymerases. The dU formed by the action of AID is removed by uracil DNA glycosylase (UNG), resulting in an abasic site. Direct replication of this abasic site involves REV1 and generates mutations at dG-dC base pairs. Recognition of dU can also result in the formation of a single-strand gap, and the filling of these gaps by polη results in mutations at dA–dT base pairs.
One important question emerges from these different roles of TLS polymerases: How TLS polymerases are regulated and integrated with DNA replication, repair, epigenetic maintenance and chromatin architecture in mammalian cells? Detailed insight into these processes is highly topical for improving new concepts into cancer development and treatment.
Group 1: TLS Polymerases and Cancer headed by Patricia Kannouche
Group 2: Genome Plasticity and B cells, headed by Said Aoufouchi
