# Novel targets of the Roberts Syndrome acetyltransferase Esco2/Eco1

> **NIH NIH R15** · LEHIGH UNIVERSITY · 2020 · $469,016

## Abstract

Project Summary
 Robert syndrome (RBS) is a severe genetic disorder characterized by phocomelia
(flipper-like appendages), microcephaly, cleft palate, syndactyly, intellectual disabilities,
seizures, and abnormalities in the heart and urinary, genital, and alimentary tract tissues.
Importantly, mutation of ESCO2 is the single and only requirement necessary to elicit this multi-
tissue and systemic suite of phenotypes. It follows that elucidating the mechanisms through
which Esco2 functions will significantly advance our understanding of pathway integrations
required for human development - from the physical to the cognitive.
 Esco2 (yeast Eco1) is an acetyltransferase that activates the DNA tethering complex -
cohesin. Esco2/Eco1 and cohesin are both essential for proper chromosome segregation. In
turn, the prevailing model of RBS (ESCO2 mutated) is that birth defects arise from mitotic failure
(massive aneuploidy) and subsequent loss (apoptosis) of proliferative stem cells and developing
tissues. Previously, we posited an alternate model in which RBS arises from transcription
dysregulation. A collaborative effort indeed discovered that Esco2 and cohesin co-regulate the
transcription of genes critical for bone growth. Thus, testing new and alternate models of Esco2
function will significantly advance our understanding of human development.
 Whether predicated on mitotic failure/apoptosis or transcriptional dysregulation, all
models of RBS focus on Esco2 acetylation of the cohesin subunit Smc3. The multi-faceted
nature of RBS, however, suggests that additional signaling pathways are at play. Here, we
report new evidence that Eco1 (yeast homolog of Esco2) may target substrates beyond
cohesins. Characterization of these novel Esco2/Eco1 substrates, and testing their roles
specifically in development, provides the first novel approach to understanding RBS, and
numerous other developmental maladies, to emerge in recent years.
 The Specific Aims of this proposal are interdependent and contain conceptually distinct
genetic approaches from which to identify novel substrates of Eco1 acetylation reactions. The
technical aspects of the two screens (an unbiased genome-wide cohesin-bypass screen and a
genome-wide conditional dosage lethality screen) are complete – with genetic interactors in
hand. In each aim, we validate the candidates, assess the acetylation state of the gene products
and dependency on Eco1, and test the importance of substrate acetylation in yeast. We then
translate findings into zebrafish embryos from which we can directly test for roles in
development and also RBS cells to test for changes in targeted substrate modifications.

## Key facts

- **NIH application ID:** 10045794
- **Project number:** 1R15GM139097-01
- **Recipient organization:** LEHIGH UNIVERSITY
- **Principal Investigator:** ROBERT SKIBBENS
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $469,016
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10045794

## Citation

> US National Institutes of Health, RePORTER application 10045794, Novel targets of the Roberts Syndrome acetyltransferase Esco2/Eco1 (1R15GM139097-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10045794. Licensed CC0.

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