# Investigating the roles of the H3.1-TSK/TONSL pathway during chromatin replication

> **NIH NIH R35** · YALE UNIVERSITY · 2024 · $464,603

## Abstract

Project Summary/Abstract
In eukaryotes, chromatin replication is responsible for the transmission of genetic and epigenetic information
between daughter cells. Interfering with this process can lead to genetic and/or epigenetic mutations, which are
both causative for many human diseases, including cancer and neurodegenerative disorders. Although
epigenetic features like histone variants, histone modifications and DNA methylation need to be properly copied
during chromatin replication, they also serve important roles in regulating DNA replication itself, as well as other
cellular processes occurring simultaneously like transcription and DNA repair. Our research group seeks to
understand the contribution of epigenetic information in regulating these processes during chromatin replication.
We are particularly interested in the roles played by conserved histone H3 variants in maintaining genomic and
epigenomic stability. Recently, we demonstrated that the replication-dependent histone H3.1 variant, which is
conserved in all multicellular organisms, directly regulates TSK/TONSL-mediated DNA repair to resolve stalled
and broken replication forks. This discovery revealed the first protein domain (the tetratricopeptide domain of
TSK/TONSL) that can “read” H3.1 to mediate a specific function at chromatin (i.e., DNA repair). One of our goals
over the next five years is to understand the impact of the H3.1-TSK/TONSL pathway in protecting the genome
against replication-associated mutations. We are also interested in elucidating the molecular mechanisms by
which TSK/TONSL initiates homologous recombination-mediated DNA repair during replication. Another related
goal is to uncover and functionally characterize other proteins that are regulated by the conserved H3.1 variant.
Finally, we aim to explore if the H3.1-TSK/TONSL interaction plays additional roles during chromatin replication
aside from DNA repair. The proposed research will reveal novel functions for histone H3 variants. In the long
term, our work will provide a better understanding of the multiple roles played by chromatin-based molecular
mechanisms in promoting the maintenance of genetic and epigenetic information. Protecting this information
during replication is critical for proper development in multicellular eukaryotes, and for preventing the occurrence
and accumulation of mutations that can negatively affect human health.

## Key facts

- **NIH application ID:** 10918047
- **Project number:** 5R35GM128661-07
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YANNICK JACOB
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $464,603
- **Award type:** 5
- **Project period:** 2018-08-07 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918047

## Citation

> US National Institutes of Health, RePORTER application 10918047, Investigating the roles of the H3.1-TSK/TONSL pathway during chromatin replication (5R35GM128661-07). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10918047. Licensed CC0.

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