# Analysis of the Mammalian DNA Damage Response

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $409,463

## Abstract

Project Summary
The DNA damage Response (DDR) is a regulatory network that coordinates cellular processed in
response to DNA damage and replication stress. It also directly orchestrates DNA repair choices by
sensing different DNA damage structures and transduces that information in cis to activate specific and
appropriate repair options, thus optimizing repair. DDR's importance is highlighted by the many cancer
predisposition syndromes resulting from its inactivation, including hereditary breast caner as well as its
role in promoting sensitivity to genotoxic chemotherapy and synthetic lethality with the successful
treatment of BRCA1/2-deficient tumors with PARP inhibitors. In the last 25 years we, and others, have
investigated the composition of the central sensing and signaling apparati that detect and respond to
genotoxic stress in yeast and now mammals. This revealed a conserved core of sensing and signaling
proteins. Our analysis of substrates of this DDR kinase cascade has revealed an extremely diverse set of
proteins and functions contacted by the DDR in mammals and the great majority of these activities are not
conserved in yeast. This includes proteins like RHINO, Abraxas, SMARCAL1, RANZB3, WHSC1,
NBA1/MERIT40, RAP80, the entire Fanconi anemia pathway including FANCI, FAN1, foci regulatory
proteins Mdc1, p53BP1, RNF8, RNF168/RIDDLIN, RFWD3 not to mention other key DDR patheays
like p53/ p21, USP28 and BDR7. Our analysis of ATM and ATR substrates and our and other's analyses
of non-ATM/ATR regulated phosphorylation events have implicated over 1000 proteins in the DDR, the
vast majority of which have no previous links to the DDR and have no yeast counterparts. Therefore, we
think there are many, many new components of the DDR to be discovered in mammals and it is critical
that we set out to identify these factors in order to generate a complete understanding of the DDR and its
significance in cellular and organismal physiology. This includes a new effort in cellular senescence, a
key response to DNA damage that prevents tumorigenesis and promotes aging. Toward this end, we have
developed sophisticated genetic tools that allow us to employ RNAi, CRISPR and ORF expression to find
new protein candidates involved in promoting survival in response to DNA damage. We have performed
three preliminary screens for loss of function and gain of function to find new DDR candidate proteins
that will serve as the basis for AIM1 and AIM2. In these AIMs we propose to carry out exhaustive
validation of the candidates to identify bona fide new DDR proteins and will follow up on two candidate
proteins already validated. In addition we have uncovered a key protein in regulation of the senescence
secretory phenotype, GATA4, which responds to ATM and ATR to activate NFkB. We will further
explore its role in senescence and a new protein required for senescence, ZNF292. These innovative
methods will allow us to deeply probe the layers of the DDR including senescenc...

## Key facts

- **NIH application ID:** 10073344
- **Project number:** 5R01CA234600-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** STEPHEN J ELLEDGE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $409,463
- **Award type:** 5
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073344

## Citation

> US National Institutes of Health, RePORTER application 10073344, Analysis of the Mammalian DNA Damage Response (5R01CA234600-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073344. Licensed CC0.

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