TLS Polymerases and Cancer

Group leader
Patricia Kannouche

Pavillon de recherche 2, Level 3

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TLS Polymerases and Cancer

Group TLS Polymerases: Genome Plasticity and Cancers

This group belongs to the team "TLS Polymerases: Genome Plasticity and Cancers" 

All cells are continuously exposed to a multitude of DNA damaging insults, which, if left unrepaired, can be life-threatening for organisms. DNA damage is particularly toxic when encountered during DNA replication, as replicative DNA polymerases are unable to replicate past DNA lesions and this can result in the stalling of replication forks, and potentially giving rise to chromosomal rearrangements if the fork collapses. To alleviate this threat, cells have evolved DNA damage tolerance strategies such as translesion DNA synthesis (TLS), which involves low fidelity DNA polymerases that can replicate damaged DNA, albeit in an error-prone manner, offering a trade-off between limited mutagenesis and chromosomal rearrangements. How DNA damage bypass pathways are regulated and coordinated with DNA replication is not completely understood.
The past 15 years have seen a dramatic advance in our understanding of how this tolerance pathway acts in response to exogenous DNA damage and how this can lead to mutagenesis. One crucial clue of the regulation of TLS relies on post-translational modifications of key effectors in the TLS reaction such as the well-documented mono-ubiquitination of PCNA by the Rad6/Rad18 complex. We and other have shown, that in human cells UVs provoke the mono-ubiquitination of PCNA at Lys164 which facilitates the translesion synthesis by recruiting TLS polymerases at stalled replication forks, providing an attractive mechanism for the “polymerase switch” at DNA lesion. 
The purpose of our research is 

  • to deciphering the regulation of these TLS polymerases (named Pol eta, kappa, iota, zeta, Rev1...) in mammalian cells, especially Pol eta which is deficient in cancer-prone xeroderma pigmentosum variant (XPV) syndrome. 
  • to define more precisely the mechanistic details of TLS process and the consequences on mutagenesis and genetic instability in higher eukaryotes.


Légende : (left) Intranuclear localisation of the TLS polymerase eta detected by immunofluorescence, (right) schematic representation of TLS process
 
Recently, we have also initiated a new line of research that aims to understand how epigenetic information is maintained during replication stress and the coordination of this process with DNA replication and the mechanisms of DNA Damage Tolerance.

Our specific approach is based on tools that combine molecular biology, cellular biology and genetics as well as genome-wide approaches such as Chip-seq and WGS. We have also developed in our lab DNA combing and iPOND techniques to decipher DNA replication dynamic in mammalian cells.

 

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