Research

Mutations are fundamental to evolution and underlie many human genetic diseases such as cancer. Studying the mutagenic mechanisms is imperative to develop novel diagnostics and therapy.

We are investigating the generation of mutations due to the unavoidable cellular phenomenon of replication-transcripiton collisions. Replication-transcription collisions result from the conflicts between the machinery of DNA replication and transcription, as both the processes use the same DNA template often simultaneously. Depending upon the relative orientation of the gene, collisions can occur in either co-directional (leading strand genes) or head-on (lagging strand genes) fashion. Collisions are shown to hamper replisome progression, cause lethal DNA breaks and recombination intermediates as well as perturb transcription. Ultimately, collisions result in genomic instability and contribute to spontaneous mutations. The mutation signatures of collisions in bacteria have been characterized to be indels (insertions/deletions) and promoter base substitutions.

I carry out my research in the laboratory of Dr. Sabari Sankar Thirupathy.

My thesis work focuses on one of the major mutagenic consequences of collisions, indels. As indels are implicated in a variety of repeat-instability genetic disorders and cancers, studying the mechanism of generation of indels will be crucial and helpful in research and clinical spheres.

Most of the idenitied mechanisms of indel generation center around replication and recombination. These include replication-strand slippage, homologous recombination and non-homologous repair pathways. However, the cellular events that trigger the aforementioned repair pathways leading to indels remain elusive. Replication-transcription collision is one such event that can lead to strand-slippage and recombination repair and these could be possible sources of collision-induced indels. Since the collision-induced mutation signatures identified in bacteria are universally observed, it is likely that the source and mechanism of indels are conserved also in higher organisms.

For my PhD, I address the following questions:

How does replication-transcription collision cause indels?

What are the genetic factors and repair pathways that operate in generation of indels?

Does collision act as a mutational process driving oncogenesis?

I will investigate these questions using robust mutation reporter assays, Sanger and next-gen sequencing, phenotypic assays and high-throughput genomics.