Improper DNA division leads to human developmental disorder: A study

The research published as an highlighted article in the Journal of Genetics used a fruit fly model to reveal about “Meier-Gorlin” syndrome, or MGS, which is a rare genetic development such as dwarfism and other skeletal abnormalities. In severe cases, MGS even results in abortions and stillbirths.
Igor Chesnokov, PhD, and his University of Alabama at Birmingham colleagues are studying this recessive, autosomal disease in an unusual way by putting mutant human genes into banana flies. Specifically, they look at one of the genes involved in MGS called Orc6.
They used this animal model to investigate the function of one human Orc6 mutation, replacement of Lysine 23 to glutamic acid (K23E), which was first reported in 2017. In humans with MGS, the K23E mutation causes a similar observable developmental disorder as Orc6 . a mutation that the Chesnokov team had previously studied, replacement of Tyrosine 225 to Serine (Y225S).
These two mutations position 23 close to the front, or the N-terminal domain, of the long chain of bound amino acids that fold to form the Orc6 protein. Position 225 is near the end, or the C-terminal domain, of the Orc6 protein thread.
Orc6 is part of the Original Recognition Complex or ORC. This complex of proteins is essential for initiating DNA reproduction in a cell, be it yeast, fly, human or any other eukaryotic organism. Without DNA division, a cell cannot divide and an organism cannot grow.
In previous research on the Y225S mutation, published in the American Journal of Medical Genetics, UAB researchers found that the C-terminal domain of Orc6 is important for protein-protein interaction to help build the ORC complex. In the current study, Chesnokov and colleagues now found that the K23E mutation in the N-terminal domain of Orc6 disrupts the ability of the protein to bind to DNA. This specific binding is an essential step in ORC function.
Although the two mutations have different underlying molecular mechanisms, they both cause the lack of pre-replication complex formation and reduced DNA replication, and they produce a similar phenotype in MGS patients.
One key in this research was to create ericimeric Orc6 genes that are part of a human gene and part of a fruit fly. It was necessary because placing a human Orc6 gene into banana flies does not prevent the lethal effect of removing Orc6 in banana flies; in other words, the intact human Orc6 cannot replace the function of the banana fly Orc6, due to the difference in Orc6 interactions with the core ORC in the two organisms.
However, when UAB researchers created a hybrid Orc6 that was human in the N-terminal domain and a banana fly in the C-terminal domain, the hybrid was able to completely save the banana flies, and they grew into adults indistinguishable from fruit. flies with wild-type Orc6. This Orc6 hybrid could then be used to test the K23E mutation in flies and study its molecular mechanism.
Chesnokov, a professor in the Department of Biochemistry and Molecular Genetics at UAB said, “This hybrid approach allows the study of human protein functions in an animal system, and it has revealed the importance of evolutionary conserved and variable domains of the Orc6 protein. that this hybrid approach not only opens a wide path to study new Orc6 mutations for medical and general scientific purposes, but could also be useful in other humanized models. “
In summary, Chesnokov stated that this humanized fly model has the unique advantage that it can differentiate test fly, human, and chemical Orc6 proteins to reveal conserved and divergent properties of the protein and its function in the cells of metazoan organisms. (ANI)