DNA replication is one of the most fundamental processes that occurs within a cell. DNA replication in eukaryotic cells requires dynamic and synergistic action of a plethora of proteins to accurately duplicate the genome. This includes, but is not limited to, precise control of replication origin activation, initiation and ensuring fidelity at replication fork, and restoration of epigenetic regulatory marks. Because DNA replication is spatiotemporally regulated in higher eukaryotes, the composition of the replisome may vary among forks depending on chromatin context, DNA sequence, three-dimensional (3D) nuclear domains, replication timing, and distinct types of fork barriers. We still do not fully understand the mechanisms underlying the regulation of chromosomal replication in humans. Our research aim is to utilize genetic approaches in combination with mechanistic biochemistry and high-throughput-omic methods to understand how the dynamics of replisome gets modulated in different genomic contexts and discern the changes in replisome composition upon different types of DNA damage, thereby ensuring genomic integrity.
Broadly, we are exploring the following key questions:
- How replisome complex is specifically organized in response to various genomic contexts?
- What are the regulatory mechanisms that decide to skip lesions and select error-prone polymerases during replication?
- Role of licensing, activation, and firing components of mammalian replication and pathophysiology of Meier-Gorlin syndrome.
- Mechanism of DNA-protein crosslinks (DPC) repair.