Low-resolution tools, which provide scant to no information on DNA damage genomic locations, have traditionally been the only option for genome integrity studies. It is possible to develop advanced next-generation sequencing methods to comprehend traditional cytological observations in DNA repair. This is because many causes of genomic instability start with endogenous DNA breaks at particular genetic sequences.
What Role Does It Play?
For an organism to survive and pass on traits to its progeny, genome integrity must be maintained. Genomic instability can result in chromosomal abnormalities and gene mutations. It is brought on by DNA damage, abnormal DNA duplication, or ad hoc cell division.
Current Research Projects on GI
- Research on chromatin topology during DNA replication and transcription and genome integrity
Genetic information transmission in organisms depends on replication and transcription mechanisms. DNA helix unwinding caused by transcription and duplication is called torsional stress. Because of this, it is essential that these processes be closely coordinated to avoid any possible conflict that could harm genomic integrity. Topological obstacles are imposed and prevent the free rotation of DNA due to the complicated chromosome structure. In addition, DNA fibres are frequently anchored to fixed structures like the nuclear envelope or the chromosome scaffold. Our efforts seek to understand these intricate processes to better understand how type I and type II topoisomerases work together to relieve topological stress brought on by replication-transcription clashes.
The genome-wide topological architecture of yeast’s transcribed genes in the G1 and S phases was recently mapped by researchers. By locking negative supercoiling at gene boundaries into a cruciform confirmation by Hmo1, they demonstrated the presence of a specific topological architecture at the coding regions that prevents supercoil diffusion. It was suggested that Hmo1 influences the gene architecture and topological memory along with Top2.
On the basis of these findings, ongoing studies seek to answer questions about RNA-DNA hybrid formation, replication termination, etc.
- DNA damage response pathway proteins facilitate mechanotransduction pathways.
ATR/Mec1, ATM/Tel1, Chk1, Chk2/Rad53, and other DNA Damage Response (DDR) proteins serve as a barrier to oncogenesis and are frequently mutated in cancer cells. ATR was crucial in earlier research for coordinating DNA replication and transcription. Specific chromatin regions’ associations with the nuclear envelope hinder chromosome condensation and replication. By phosphorylating the essential nucleoproteins during replication, ATR detaches transcribed chromatin from the NE. This avoids the build-up of topological constraints where forks come into contact with transcribed genes gated to the NE. When transcribed genes are not detached from the NE, replication forks collapse and reverse. More recently, it was discovered that ATR is required for cell mechanics and nuclear integrity during interstitial migration. It is a part of the NE-mediated mechano-transduction system that responds to topological stress in prophase or S phase.
- Ageing, metabolism, and DDR
The fundamental biological process of metabolism, which is necessary for cellular survival, also produces metabolic byproducts that damage DNA, including reactive oxygen species. (ROS). Cellular metabolism and the DDR mechanism are closely related, according to research conducted over the last ten years. Cancer cells exhibit significant metabolic rewiring and altered DDR pathways, underscoring the significance of research efforts in this field.
Current lab research focuses on the interaction between metabolism and nuclear mechanotransduction. It also focuses on metabolic rewiring during ageing and its link to oncogenesis. It also emphasizes on metabolic cues that lead to chromosome packing and genome integrity.
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