# Mechanisms of cohesin regulation in vertebrates

> **NIH NIH R35** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $426,250

## Abstract

Project Summary/Abstract
In vertebrate cells the cohesin protein complex plays critical roles in nuclear structure and function. It tethers
together the identical products of DNA replication, called sister chromatids, until cell division and it also
mediates intra-chromosomal bridging interactions, forming chromosome loops and domains. While cohesion
between sister chromatids is critical for accurate chromosome segregation and certain kinds of DNA repair, the
compaction of chromosomes into loops and domains is essential for proper transcription and normal
development. How these different kinds of cohesion differ at the molecular level, the mechanisms that ensure
each outcome, and the amount of overlap between them are not well understood. The existence of multiple
orthologs of a number of cohesin subunits and regulators, as well as the presence of Sororin, which is unique
to metazoans, suggest complexity of cohesin regulation in higher eukaryotes. Our work addresses several key
challenges in the field: 1) how are DNA replication and cohesin regulation properly integrated in vertebrate
cells, 2) how do vertebrate-specific elaborations of the cohesion apparatus contribute to function, and 3) how
can cohesin be remodeled locally to ensure specific outcomes, such as changes in gene expression or access
and function of DNA repair machinery. As previously, we will continue to work in multiple systems as
appropriate, including genome-modified cultured cells, cell free lysates from frog eggs, frog embryos, and
purified proteins in vitro. Our strength lies in using molecular genetic approaches that allow us to test directly
the impacts of specific interactions, in all of these experimental systems. By following up on our recent work, at
the end of this next funding period we hope to fully understand how the ESCO1 and ESCO2 vertebrate
cohesin modifiers, through their strikingly unstructured domains, stabilize cohesion in a context-specific
manner. We will also define how proteins at the DNA replication fork, particularly the initiation factor TICRR,
impact cohesin stabilization, and the regulation of this process during early development. Finally, we will exploit
a tractable model for site-specific DNA damage to characterize the contributions of vertebrate cohesin
regulators and modifications to damage-induced local cohesin remodeling and thus genome maintenance.

## Key facts

- **NIH application ID:** 10819550
- **Project number:** 5R35GM149343-02
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Susannah Rankin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $426,250
- **Award type:** 5
- **Project period:** 2023-04-03 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819550

## Citation

> US National Institutes of Health, RePORTER application 10819550, Mechanisms of cohesin regulation in vertebrates (5R35GM149343-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10819550. Licensed CC0.

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