Genome stability

Underlying Mechanisms

Aims

The WP « Genome Stability » of ONCOAGE has built an interdisciplinary proposal that will:

(1) investigate how DNA and chromatin alterations drive ageing and age-related pathologies;

(2) develop innovative genomic biomarkers and assays to evaluate frailty in elderly patients, to model age-related pathologies, including cancer,  and to screen anti-ageing as well as anti-cancer drugs.

Leader name(s)

Pr E. Gilson

General description

The maintenance of genome integrity, both at the DNA and chromatin level, is a fundamental aspect of life. Cells respond intrinsically to the perception of genome damages by initiating various surveillance mechanisms (i.e. the DNA damage response or DDR) that determine tissue homeostasis by transcriptional changes, cell cycle regulation, growth arrest, repair attempts, metabolism switch and activation of immune response. However, these mechanisms eventually fail, leading to accumulation of DNA and chromatin alterations, which are key drivers of ageing. Many unknowns remain in our understanding of the genome surveillance systems during ageing, cancer and age-related degenerative pathologies and how these changes can be translated in medical practice.

Due to the pivotal role of genome stability in ageing and cancer, the innovative concepts and state-of-the art tools developed here will lead to publications in high-impact journals and will open new opportunities for fundamental and translational researches, for ageing teaching programs, for industrial valorisation and for clinical trials.

Task Title
(Epi)genomics of tissue regeneration
Task Description

A fundamental characteristic of ageing is the reduced capacity to adequately maintain tissue homeostasis or to repair tissues after injury with advancing age.

The goals here are to determine:

  1. how telomerase masters kidney epithelium reprogramming;
  2. how non coding (nc) RNAs control the renewal of airway epithelial cells and how failure of this epigenetic mechanism leads to age-related lung diseases.
Task Improvement
  • Identification of epigenetic mechanisms that control kidney and lung regeneration.
  • Understanding the non-canonical functions of telomerase in regulating signalling pathways that are critical for regeneration.
  • Deciphering the regulatory function of ncRNAs in fibrogenesis process and its impact on early-stage lung tumours aggressiveness.
  •  Reachable in 5 years
Task Title
Mechanisms linking genome instability to age-related degenerative pathologies
Task Description

Genome instability account for a large spectrum of clinical presentations, including premature ageing syndromes and degenerative disorders. The goals here are:

  1. to determine the role of MFN2, CHCD10 as well as the helicases TWINKLE and Pif1 in mitochondrial (mt) DNA stability;
  2. to identify new genes involved in mtDNA instability disorder;
  3. to study the impact of genetic, and epigenetic alterations as well as mtDNA and telomeric abnormalities arising with age in patients suffering from facio-scapulo-humeral muscular dystrophy (FSHD) and inclusion body myositis (IBM).
Task Improvement
  • Identification of genetic and epigenetic mechanisms involved in rare  degenerative neurological and neuromuscular diseases.
  • Identification of biomarkers for diagnosis improvement and development of therapeutics for rare age-related diseases.
  • Conceptual and methodological advances that can be transferred for the benefit of the general population suffering from other diseases associated to ageing.
  • Reachable in 4 years
Task Title
Telomeres as frailty biomarkers
Task Description

This task combines the expertise of onco-geriatricians in evaluating patient frailty and of fundamental researchers in telomere biology. It aims at:

  1. exploring the possible correlations between several clinical parameters used by geriatricians and oncologists together with the molecular evaluation of telomeric status (biomarkers of ageing);
  2. Evaluating the gerontogenic impact of anti-cancer treatments (chemotherapies and targeted therapies).
Task Improvement
  • Defining new ways to detect frailty Establishing telomeres as a potent and unbiased biomarker for ageing.
  • A better and earlier evaluation of frailty for therapeutic course decisions and outcome anticipation regarding elderly patients, individualizing the benefit/risk balance evaluation.
  • Reachable in 3 years
Task Title
DNA damage response and epigenetic reprogramming during oncogenesis
Task Description

In order to study the functional relationships between DDR and chromatin remodelling during oncogenesis, we will study:

  1. the mechanisms and consequences of telomere dysfunction and retrotransposon reactivation (LINE-1) in tumours;
  2. the changes in the chromatin landscape of Carcinoma-Associated Fibroblasts (CAF);
  3. how the DDR remodels the chromatin and positively regulates the transcription of genes involved in tumour relapse and metastases;
  4. the function in treatment-resistant forms of cancer of a new form of phospho-Ku70, an essential DNA repair component;
  5. the role of the “Cancer Stem Cell” marker CD24 in genetic instability and emergence of radiation-resistant cancer cells.
Task Improvement
  • New mechanisms of malignant transformation;
  • New biomarkers for cancer aggressiveness, therapeutic strategies and relapse.
  • Reachable in 3 years