Luis Blanco
The group of Luis Blanco studies the only two DNA polymerases involved in double-strand break repair in humans, Pol lambda and Polµ (mu), which were both identified in his laboratory in 1999. These enzymes are relevant to maintain the equilibrium between genome stability and the levels of variability required, not only for evolution, but also for the normal function of specific genes. Moreover, dysregulation of these enzymes could be responsible for the mutator phenotype associated to carcinogenesis. In this project, a direct role of Pol lambda and Pol mu in the repair of DSBs produced in the vicinity of the replication fork will be evaluated. For that, we will study the specificity of the interactions of both polymerases with NHEJ proteins, and with the eukaryotic processivity factor PCNA, and how these interactions are regulated during DNA replication and repair. A S. pombe model lacking Pol IV will serve us to perform complementation analysis with its human orthologues, and to study the possible role of NHEJ in the activation of replication origins.

The group of José Antonio Tercero is interested in the mechanisms involved in regulating chromosome replication in the presence of DNA damage, and how the S-phase checkpoint plays a key role in this process. These studies, that will be carried out in S. cerevisiae, are important in a wider context as the mechanisms of DNA replication and DNA damage response are conserved from yeast to humans.

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Figure 1: Modular organization of various DNA polymerase X from different organisms.
With the exception of the African swine fever (VPPA) PolX, all members share a Polß core containing polymerization (blue) and 8 kDa (orange) domains. Those 8 kDa domains with an intrinsic dRP lyase activity, and therefore with a potential or demonstrated role in BER, are hatched. The four PolX members present in humans are Pol lambda, Pol µ, TdT and Polß (yellow background area). Three of them contain a N-terminal BRCT domain, that allows these enzymes to interact with NHEJ factors, for their roles in NHEJ and/or VDJ recombination. The yeast (Sc and Sp) Pol IV has a Pol lambda-like architecture. The bacterial PolX (Bs, Bacillus subtilis; Mt, Methanococcus thermoautotroficum) have a phosphodiesterase domain at their C-terminus. The entomo-poxvirus PolX (MSEV) has a AP-endonuclease domain at its N-terminus.