Georgios Pappas - ESR 7Georgios Pappas

Nationality:  Greek

Main Host Institution:  Danish Cancer Society Research Centre, Copenhagen, Denmark

Academic background:  

  • Bachelor degree in ‘’Biology’’, University of Patras, Patras, Greece
  • Master degree in "Molecular Medicine’’, National and Kapodistrian University of Athens, Greece 

Project title:  Novel ubiquitylated DDR factors in DNA repair and response to Replication Stress

Project background:  Genomic instability constitutes a major cancer hallmark being responsible for cancer initiation and progression. The main endogenous source of genomic instability and subsequently of elevated mutagenesis is replication stress. This stress has been partly characterized in many types of cancer and found to commonly originate from deregulation of oncogenes and tumour suppressor genes which drive constitutive/aberrant replication. Cancer cells have adapted their metabolism to respond to this condition by triggering specific pathways of the DNA Damage Response (DDR) cascade, shaping their aggressive hallmarks. Extended DNA damage that is triggered by DNA replication stress in cancer cells, is not lethal but results in selective killing of these cells when combined with inactivation of a second tolerance gene, under the concept of Synthetic Lethality.

RNF8 and RNF168 constitute crucial mediators of DNA damage response within the cells and therefore they are associated with tolerance to replication stress exerting their roles via their E3 ubiquityl ligase activity. However, their substrates of ubiquitylation are poorly understood- except from histones- and remain to be proven.

Elucidation of the function of these substrates will provide a further mechanistic insight of the role of these E3 ligases in the responses of cancer cells to replication stress. This will possibly indicate new candidate drug targets for cancer specific therapies under the prism of Synthetic Lethality.

Project aim: 

  • Validation of the most promising hits from our pan-proteomic, SILAC based screen for novel candidate substrates of the E3 ligases RNF8 and RNF168
  • Elucidation of functions of selected candidate RNF8/168 substrates in responses of cancer vs. normal cells (breast and ovary) to DNA damage and Replication Stress

Expected outcome:  Novel insights into DDR mechanisms, particularly the functions of RNF8/168 and their substrates of ubiquitylations in responses of normal and cancer cells to DNA damage and Replication Stress.