Michael J. Bertram, Ph.D.
University of Alabama at Birmingham

Genetic Analysis of the MORF4 Related Gene Family in Drosophila: Insights into Cellular Senescence.

In vitro cellular senescence, since its first description in the literature, has been put forward as a model for aging in species with mitotically active tissues. Evidence suggests that sub-lethal levels of DNA damage, including telomere loss, induce the cellular senescence phenotype in normal human cells. Cellular senescence results in irreversible cell cycle arrest, morphological changes at the cellular level, and a shift in gene statement. In contrast, immortal cell lines divide indefinitely in culture and have lost the ability to induce the senescence pathway. Senescent cells have been demonstrated to be resistant to apoptosis in vitro and accumulate with age in vivo. These accumulating senescent cells with in tissues may act to compromise tissue function as well as structural integrity resulting in overt phenotypes associated with aging. Previous studies have indicated that the senescence pathway is genetically dominant over immortality and that four genetic complementation groups, A, B, C, and D, control the induction of cellular senescence. The activation of the genes in the complementation groups is thought to be induced by the DNA damage and genomic instability resulting in, and associated with unregulated cell division.

The human cellular senescence gene MORF4 and the highly conserved MORF4 related gene (MRG) family are subunits in multimeric histone acetyltransferase (HAT) complexes. MORF4 was identified based on its ability to induce senescence specifically in human Group B immortal cell lines. Based on MORF4’s amino acid sequence and statement pattern in comparison to the predominant human MRG family proteins, MRG15 and MRGX, it may function to redirect the complex to different genes in response to DNA damage. In support, the S. cerevisiae MRG homolog, EAF3p, as part of the NuA4 HAT complex targets the activation of specific genes. In addition, the homologous human HAT complex, the Tip60 complex is shown to play a role in DNA damage repair and induction of apoptosis. The human MRG family member MRG15 physically interacts with the retinoblastoma protein (Rb) further strengthening the MRG protein family to the DNA damage response and cell cycle control.

I have identified MRG family members in twenty-one eukaryotic species including Drosophila melanogaster. The similarity at the protein level is significant and suggests that the function of the MRG proteins is conserved from fruit flies to humans. A null mutation in the MRG15 homolog of Drosophila results in homozygous recessive lethality. Using the powerful genetic and molecular techniques available in Drosophila, my research will determine the functional conservation between human and Drosophila MRG15 homologs and to identify genetic and molecular MRG family interactors. This will include targeted analysis of candidate genes, such as the Drosophila homologs of the human Tip60 HAT, Rb and TGF-ß proteins, and genetic and functional screens for novel interacting genes and proteins. New insights into the role of MRG family proteins in DNA damage response and cell cycle control will be obtained by identifying and characterizing MRG family interactions in Drosophila. This will in turn provide a better understanding of cellular senescence and its role in aging in humans.

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