# Nuclear dynamics maintaining chromatin integrity during DNA replication

> **NIH NIH R35** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $382,121

## Abstract

PROJECT SUMMARY
The human genome is organized in 3-dimensional (3D) space, with spatially-distinct nuclear regions creating
higher-level order that controls essential processes. For example, DNA replication occurs within nuclear foci that
are spatially-separated from transcription condensates that contain active gene promoter and enhancer
elements. Indeed, replication and transcription exhibit remarkable coordination ensuring genetic and epigenetic
information are conserved upon cell division. Transcription condensates are temporally dynamic and undergo
reorganization throughout S phase. How this level of control is achieved is poorly understood, and thus, it is
unknown how replication and transcription remain spatially separated to prevent transcription-replication conflicts
(TRCs) that destabilize the genome. We are uniquely positioned to answer this question given our recent
progress uncovering ATR (ataxia-telangiectasia and rad3-related), a DNA damage checkpoint kinase, as a key
regulator of transcription condensate function. ATR accumulates within condensates during S phase, signals a
change in condensate composition, and alters the RNA polymerase II transcription cycle. Moreover, acute
inhibition of ATR increases TRCs suggesting its function in transcription condensates is critical for coordinating
replication and transcription. Interestingly, we have observed a subset of ATR-regulated condensates to co-
localize with histone locus bodies, where the replication-dependent histones are transcribed and the resulting
pre-mRNAs are processed coupling histone biosynthesis to S phase. Intriguingly, loss of ATR deregulates
multiple steps of histone production and elevates histone levels correlating with a shutdown of replication and
the appearance of markers of global replication catastrophe. This raises the question as to whether disruption of
histone biosynthesis is a key driver of replication catastrophe upon loss of ATR signaling. We will answer this
question and uncover the ATR-dependent mechanisms that couple histone biosynthesis within nuclear bodies
to S phase. Our exciting progress stands in contrast to the classical view of ATR signaling as predominantly a
driver of the replication stress response and implicates ATR as a key regulator of nuclear dynamics in 3D space
during S phase. Finally, we will develop a novel 3D chromatin conformation technology to study how replication
of transcriptionally-active regions impacts promoter-enhancer contacts. We will use the technology to elucidate
the mechanisms that promote re-establishment of 3D interactions post-replication and ensure faithful
transmission of 3D genome organization and the transcriptional identity of cells across S phase. In sum, my
research program over the next five years will lead to important discoveries as to how cells maintain
transcriptional states and genome organization during the highly dynamic period of S phase.

## Key facts

- **NIH application ID:** 10501685
- **Project number:** 1R35GM147710-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Joshua Saldivar
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $382,121
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501685

## Citation

> US National Institutes of Health, RePORTER application 10501685, Nuclear dynamics maintaining chromatin integrity during DNA replication (1R35GM147710-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10501685. Licensed CC0.

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