# Characterizing the effect of transcription-replication conflicts on transcription and co-transcriptional processes

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2024 · $396,250

## Abstract

PROJECT SUMMARY
Coordination between the replication and transcription process is one of the major challenges that cells face during
proliferation. As both replication and transcription machinery use the same genomic DNA as a template, to avoid conflicts,
spatial-temporal separation between these two processes is necessary. Cells have evolved different mechanisms to evade
conflicts but several physiological contexts such as the proximity of transcription start site to replication origins or diverse,
adaptive transcription programs throughout different cell types together with the vast number of replication origins in human
cells make distinct demarcation between these two processes hard to achieve. Moreover, several pathological conditions
such as oncogene activation during cancer onset further complicate matters by altering the replication and transcription
program and inducing transcription-replication conflicts profusely. Transcription-replication conflicts are known to perturb
DNA replication and induce DNA damage and genome instability. Although how these conflicts affect the other key
component of the conflicts, RNA polymerase II (RNAPII), its elongation speed, or transcription in general remains
completely unexplored. Moreover, RNAPII speed or transcription kinetics regulate critical co-transcriptional processes such
as alternative splicing, alternative polyadenylation, and transcription termination, thus regulating the production of
alternative splice variants, circular RNAs, alternatively polyadenylated transcripts, or read‐through transcripts. Hence,
alteration in just RNAPII speed could lead to the expression of different isoforms of proteins with potential physiological
significance. My long-term goal is to understand the regulation of multiple aspects of transcriptional and co-transcriptional
processes by transcription-replication conflicts and DNA damage in general especially during tumorigenesis. Moreover, I
aim to enhance our understanding of how cells use different mechanisms to deal with the conflicts at different regions of
the genome and how these pathways, dedicated to resolve conflicts, are coordinated.
 In the next five years, my proposal, for the first time, will systematically explore the effect of transcription-
replication conflicts on transcription, investigate the role and significance of RNAPII speed in maintaining cellular fitness,
and characterize the mechanistic role of the Integrator complex on the conflicts. Integrator is a transcription processing
machinery that I recently discovered to have the ability to mitigate the damaging effects of transcription-replication
conflicts.
 I anticipate that these studies will act as a platform for future efforts to understand the interplay of transcription and
replication in controlling cellular homeostasis. Broadly, this work is part of a larger effort by my lab to understand whether
conflicts are a regulated process, triggering cellular changes of physiological significanc...

## Key facts

- **NIH application ID:** 10940759
- **Project number:** 1R35GM155237-01
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Rahul Bhowmick
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $396,250
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940759

## Citation

> US National Institutes of Health, RePORTER application 10940759, Characterizing the effect of transcription-replication conflicts on transcription and co-transcriptional processes (1R35GM155237-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10940759. Licensed CC0.

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