# Identifying chromatin factors essential for DNA repair using a novel high-throughput screening methodology

> **NIH NIH K99** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $109,080

## Abstract

PROJECT SUMMARY
Mammalian cells are continually exposed to environmental toxicants including UV-radiation and various sources of
ionizing radiation (IR) threatening genomic integrity, leading to an increased risk of cancer and neurodegenerative
disease. Given our constant exposure to environmental toxicants, elucidating fundamental principles of genome
integrity maintenance is critical for developing therapeutic interventions for a host of age-related pathologies. In recent
years, several chromatin-based events have been shown to be critical mediators of an effective DNA damage
response (DDR), however the lack of high-throughput screening methodologies have significantly hampered the
identification of chromatin factors essential for DNA repair. To address this, this proposal will use a newly developed
high-throughput screening methodology, coupled with a cDNA library of predicted chromatin interactors
(“ChromORFeome”), to identify novel chromatin factors involved in DNA repair. During the mentored (K99) phase of
this proposal, the candidate will determine the importance of a newly identified chromatin-interacting protein,
ZNF280A, for the repair of DNA damage, identifying specific repair pathways which require ZNF280A (Aim 1).
Preliminary data demonstrates that ZNF280A is recruited to sites of DNA damage induced by a variety of sources
including ionizing radiation (IR). The candidate will build upon this data to determine mechanistically how ZNF280A
orchestrates DNA repair (Aim 2A) and ascertain whether this contributes to therapy resistance in pancreatic ductal
adenocarcinoma (PDAC), where increased expression of ZNF280A correlates with significantly poorer outcome in
patients (Aim 2B). Importantly, while in the mentored (K99) phase, the candidate will take advantage of the resources
available at Massachusetts General Hospital for professional development, applying these skills through mentoring,
data presentation and writing opportunities. During the non-mentored/independent research phase (R00) of the
project, technical skills and reagents developed by the candidate during the K99 phase will be used to elucidate the
importance of ZNF280A in the 22q11.2 deletion human syndrome. ZNF280A resides at the 22q11.2 locus and
preliminary data demonstrates that depletion of ZNF280A results in spontaneous DNA damage. The candidate will
therefore investigate the importance of ZNF280A for the resolution of DNA replication stress and determine whether
this can mechanistically explain some of the features of 22q11.2 deletion syndrome (Aim 2C). In addition, very little is
known about how chromatin structure and function is re-established following DNA repair. Therefore, in the R00 phase
the candidate will extend these approaches and utilize the high-throughput screening methodology to identify novel
chromatin factors involved in the late stages of DNA repair (Aim 3). These experiments will provide the candidate with
data for an early independent publication a...

## Key facts

- **NIH application ID:** 10505883
- **Project number:** 1K99ES034443-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Thomas L Clarke
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $109,080
- **Award type:** 1
- **Project period:** 2022-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505883

## Citation

> US National Institutes of Health, RePORTER application 10505883, Identifying chromatin factors essential for DNA repair using a novel high-throughput screening methodology (1K99ES034443-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10505883. Licensed CC0.

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