CG Research Areas

The Center for Genomics was established after Zewail City launched the Genome Initiative at Helmy Institute for Medical Sciences. It employs the latest cutting-edge research combining genetics, biochemistry, cellular and molecular biology, and whole animal studies. Research areas are primarily dictated by our scientists and revolve around four main themes:

  • Gene-environment interaction, with particular emphasis on pollution.
  • Understanding how genomes function in health and disease.
  • Identification of new gene functions.
  • Improvement of human health using the knowledge obtained from our research studies.

 

The center's research areas include but are not limited to:

  • Oxidative-stress induced chromosomal breaks, DNA-damage repair and human degenerative disease.
  • Nuclear versus mitochondrial DNA repair in health and disease.
  • Protein-linked chromosomal break repair, cancer and neurodegeneration.
  • The relationships between genome stability, hormone homeostasis and metabolic disorders.
  • Genetic and high-throughput screening for the identification of novel gene functions.
  • Correlation between the level of unrepaired breaks and neurological decline, longevity and cognitive function.
  • Integration of genomics with transcriptomics, proteomics and metabolomics for the generation of disease-specific profiling.
  • Genome stability, cancer formation and therapy.
  • Genome stability in stem cells in relation to conventional chemo- and radio-therapy.
  • Genomics and regenerative medicine.
  • Genomics and appetite suppressants as tools for tackling obesity.

 

Ongoing Research Activities

 

The inappropriate repair of DNA breaks can result in deleterious consequences leading to genetic instability and cancer. During the normal catalytic cycle, DNA topoisomerases become attached to the DNA 3’-end (Top1) or 5’-end (Top2) via a covalent phosphotyrosyl bond. Collision of these intermediates with DNA or RNA polymerases generates irreversible protein-linked DNA breaks (PDBs). The repair of PDBs requires the removal of the covalently linked topoisomerase, which is achieved by an ‘error-prone’ mechanism (nucleolytic cleavage and loss of genetic material) or an error-free mechanism (hydrolytic cleavage of the phosphotyrosyl bond linking the topoisomerase to DNA).

The prototype enzyme for the latter activity is tyrosyl DNA phosphodiesterase 1 (TDP1), which primarily removes Top1 from DNA termini. More recently, we identified the corresponding activity that repairs Top2-breaks and subsequently named it TDP2. Emerging evidence suggests that TDP1 and TDP2 fulfill overlapping functions in mammalian cells to ensure error-free repair, and that loss of these mechanisms may predispose to cancer. Another common form of endogenous DNA damage is oxidative attack by reactive oxygen species (ROS), which can also trap DNA topoisomerases on DNA, resulting in PDBs. A subset of oxidative DNA breaks (ODBs) may be direct substrates for TDP1, such as those with 3’-phosphoglycolate termini.

In addition to their role in tumorgenecity, the accumulation of PDBs or ODBs underlies the clinical efficacy of a wide range of anti-cancer strategies. For example, topoisomerase poisons and ionizing radiation kill cancer cells by trapping topoisomerases on DNA and/or by generating oxidative DNA damage. Consequently, key players in these pathways are attractive anti-cancer targets, such as topoisomerases, poly (ADP-ribose) polymerase (PARP), TDP1 and TDP2. At the Center for Genomics we will characterize the mechanisms of repairing this type of DNA breakage and use this knowledge to improve cancer therapy.

In addition, we will identify novel players in this process that will lead to innovative methods for the treatment of cancer. For example, recent work from our lab has led to the initiation of a drug discovery program for the development of small molecule inhibitors used in a number of clinical applications.

 

The putative role of DNA repair deficiency in the pathogenesis of several neurological disorders has been the subject of intense scientific scrutiny. Ataxia telangiectasia (AT) is the prototype example of such disorders, and yet it is still not completely understood why deficiency of the protein mutated in AT (ataxia telangiectasia mutated, ATM) leads to the severe neurological abnormalities seen in this disorder. Cerebellar degeneration is the most common neurological presentation of AT, which is also a shared feature among at least three distinct hereditary diseases: spinocerebellar ataxia with axonal neuropathy 1 (SCAN1), ataxia oculomotor apraxia 1 (AOA1) and ataxia oculomotor apraxia 2 (AOA2). A unique feature of the cerebellum is its extended postnatal development.

During this phase of growth, rapid cell proliferation is expected to generate replication stress, leading to more DNA breaks than in other parts of the nervous system. Whether this explains the selective degeneration of the cerebellum in AT, SCAN1, AOA1 and AOA2 is yet to be determined. Although SCAN1, AOA1 and AOA2 share most of the neurological presentations, they lack the cancer predisposition and immunodeficiency observed in AT. However, there is a fair degree of overlap in the extra-neurological features (fig 2).

For example, while AT and AOA2 patients present with high levels of alpha fetoprotein (AFP), SCAN1 and AOA1 patients present with reduced levels of serum albumin. It is unknown whether this is a consequence of the associated DNA repair defect or a result of a progressive functional decline.

Currently, the understanding of nuclear–mitochondrial interactions is limited and the role of mitochondrial DNA (mtDNA) repair proteins remains contentious. For example, mtDNA has no capacity for independent replication and relies on nuclear-encoded DNA polymerase gamma. In addition, several components of the DNA repair machinery possess mitochondrial versions that are also encoded by nuclear genes. For example, Lig3a, APE1, APE2 and Cockayne syndrome B (CSB) have been shown to localize to mitochondria. Based on estimates of the number of mitochondrial genes residing in the nuclear genome, around a tenth of the population may be carrying genetic disorders that could affect mitochondrial function. In this context, mitochondrial DNA repair defects could contribute to neurological decline and aging.

Defects of mtRNA maturation have also been associated with an autosomal recessive spastic ataxia with optic atrophy, which highlights the importance of RNA integrity for mitochondrial function.
Aging is regulated by the extent of stochastic damage that accumulates over time and the rate at which this damage accumulates. The latter is dictated by the efficiency of genetic pathways that control longevity. Mitochondrial function is a key player in these mechanisms. This was first suggested in Drosophila and subsequently in mammals where age-dependent accumulation of mutations within mtDNA was reported.

DNA deletions have also been shown to cause premature aging in mitochondrial mutator mice. The link between DNA damage/repair and aging is also rapidly emerging and was first highlighted by the premature aging-like syndromes that are associated with defects in DNA repair, such as defects in nucleotide excision repair.

How do unrepaired breaks lead to neuronal dysfunction? What is the relative contribution of mitochondrial and nuclear DNA repair to neurological dysfunction? It is worth noting that brain specific deletion of the ‘nuclear’ scaffold protein XRCC1 leads to cerebellar defects in mice. Do mitochondria require similar scaffolding factors? What is the relative proportion of physiological levels of nuclear and mitochondrial protein-linked breaks? Why isn’t human DNA ‘programmed’ to regrow neural cells as it ages? These are a few examples of the ongoing challenges we face.