# Novel Mechanisms and Regulation of Mammalian Double-Strand Break Repair

> **NIH NIH R35** · THOMAS JEFFERSON UNIVERSITY · 2024 · $629,912

## Abstract

Project summary.
Cell proliferation under normal and adverse environmental conditions depends on multiple DNA damage
response (DDR) pathways. Replicative stress and cellular exposure to genotoxic agents can lead to double-
strand breaks (DSBs) which are the most lethal DNA lesions. Major DSB repair (DSBR) pathways include error-
prone non-homologous end-joining (NHEJ) and accurate homology-directed repair (HDR) which promotes
genome integrity and tumor suppression. Microhomology-mediated end-joining (MMEJ), also referred to as
alternative end-joining (alt-EJ) and polymerase theta-mediated end-joining (TMEJ), is the most recently
discovered DSBR pathway that contributes to genome instability and cancer cell survival. Over the last 15-20
years, basic research of DSBR has arguably led to some of the most important advances in the history of
biomedical science and biotechnology, such as the development of Poly ADP ribose 1 (PARP1) inhibitors as
precision medicine for HDR-deficient cancers, and genome engineering involving CRISPR-Cas9 which was the
subject of the 2020 Nobel Prize in chemistry.
 Dr. Pomerantz’s lab has strongly contributed to advancing our knowledge of the molecular mechanisms
of MMEJ based DSBR over the past 10 years, and has significantly contributed to advancing our understanding
of RNA-templated DSBR (RNA-DNA repair) over the past 5 years. For example, Dr. Pomerantz’s lab recently
identified a new MMEJ repair pathway involving Poll, and discovered that human Polq exhibits reverse
transcriptase activity and promotes RNA-DNA repair in human cells. To significantly advance our basic
knowledge of some of the most intriguing and important areas of DSBR, the Pomerantz lab proposes to continue
to address the following three questions: 1. Does RNA directly contribute to DSBR? 2. How are DSBR
proteins structurally and chemically regulated? 3. Do undiscovered DSBR pathways exist and contribute
to genome instability/integrity?

## Key facts

- **NIH application ID:** 10765130
- **Project number:** 1R35GM152198-01
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Richard T Pomerantz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $629,912
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765130

## Citation

> US National Institutes of Health, RePORTER application 10765130, Novel Mechanisms and Regulation of Mammalian Double-Strand Break Repair (1R35GM152198-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10765130. Licensed CC0.

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