Sree Chaitanya
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Biosketch
Our cells and their DNA must multiply rapidly during growth, injury, and aging – with millions of new cells made every minute in our bodies. While on the one hand, the replication of the DNA occurs, on the other, the transcription machinery constantly reads the information in the DNA making its alter-ego – RNA. Hence, collisions between the types of machinery responsible for transcription and replication can be detrimental to cells and may lead to pathological conditions (e.g., cancer). Therefore, cells evolved sophisticated control mechanisms to prevent such collisions.
One of these control mechanisms helps in the surveillance and timely removal of peculiar nucleic acid structures called R-loops or hybrids of RNA and DNA that form during transcription and can interfere with DNA replication. In fact, scientists have shown that failure to do this impacts the accuracy of transcription and replication. Defects in this ‘RNA-based surveillance system’ could underlie some mutations and genomic chaos often observed in cancer cells. (Fun fact: The widely popular genetic tools like RNA interference and CRISPR/Cas are a product of RNA-based genome surveillance systems).
During my PhD. and postdoc, our data provide a novel framework for interpreting the reciprocal interactions between transcription and DNA damage at distinct chromatin regions. We initially reported that Histone methyltransferase SETD2 (H3K36me3 writer) coordinates nucleosome dynamics during transcription (PMID: 23325844) and further regulates DNA double-strand break repair in transcriptional units (PMID: 24843002). However, I was particularly interested in understanding how cells sense co-transcriptionally formed RNA-DNA hybrids or R-loops. Encouraged by my advisor (Sérgio Almeida) to think and work independently, we report that aberrant pausing of RNA polymerase II initiates a signaling cascade that culminates in the suppression of R-loops (PMID: 28076779).
Also, at the onset of double-strand breaks, paused RNA polymerase II can signal DNA repair factors (PMID: 30541148) or trigger non-canonical transcription in the gene body (PMID: 30662944). Surprisingly, we also found intron evolution as a strategy to alleviate opportunistic R-loops (PMID: 28757210). On a different note, I contributed to understanding the protein-protein interaction (between a nuclear phosphatase and an actin-binding protein) that is crucial for the formation and dynamics of actin cables required to drive nuclear positioning during cell migration (PMID: 33567288).
Testimony
Working at the iMM and living in Lisboa was one of the best things that happened in my life either personally or professionally. iMM is where I took my first steps to learn the nuances of scientific investigation. I also happen to work in a young and productive lab supported by great mentors.
The networking opportunities I secured with the prestigious Marie Skłodowska-Curie Actions Ph.D. fellowship were crucial in my further career steps. The extremely supportive scientific and administrative staff made my life very easy. iMM was also very welcoming to foreign students; if I am right, I may be the first Indian student to do a Ph.D. at the iMM.
Last but not least, I met some of my best friends for life – a bond I will cherish forever. I always love to come back to Lisboa and visit my alma matter.
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