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.
Contact Dr. Bertram