# DNA Damage & DNA Replication: a Complex Relationship

> **NIH NIH R35** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $949,600

## Abstract

PROJECT SUMMARY/ABSTRACT
Our overarching goals are: i. to define the mechanism(s) of ATM activation by the Mre11 complex; ii. to
define the role(s) of the Mre11 complex in DNA replication; iii. To define the role(s) of the Mre11 complex in
response to DNA replication stress. As part of the emphasis of DNA replication stress, our focus includes
RTEL1 which acts to mitigate replication stress at the telomere. A combination of yeast and mouse genetics,
biochemistry, and structural biology are employed to address these issues. Our previous work on these topics
led to substantial scientific progress and insight regarding processes relevant to human health. Specific areas
of inquiry are:
 • Genetic screens in yeast and mining of cancer genomic data revealed separation of function Rad50
 mutations that affect ATM dependent DNA damage signaling without affecting the DNA repair functions
 of the Mre11 complex. These mutations constitute a resource for deciphering the mechanism by which
 the Mre11 complex activates the ATM kinase to initiate DNA damage signaling.
 • We have modeled three recurrent tumor borne mutations in mice that were confirmed to be
 hypomorphic for ATM activation but proficient in DNA repair. These animal models offer a unique
 opportunity to delineate Mre11 complex-dependent ATM functions.
 • We have identified factors that function at the DNA replication fork in a manner that depends on the
 Mre11 complex. An important focus of our laboratory is to understand the functional role(s) of those
 factors. Defects in factors that promote accurate DNA replication are highly correlated with human
 disease, and so understanding this fundamental process is an important priority in our work.
 • Whereas the Mre11 complex functions at the replication fork, RTEL1 is a helicase that promotes
 accurate replication of telomeric DNA. We have discovered that RTEL1 influences the abundance and
 disposition of a long non coding RNA, called TERRA, that is transcribed from the subtelomeric regions
 of all eukaryotes. Our goal in this aspect of our work is two fold. First, to understand the role of RTEL1
 in maintaining telomere stability. Second, to use that information to shed light on the function of
 TERRA, which is a long standing question.

## Key facts

- **NIH application ID:** 10221003
- **Project number:** 5R35GM136278-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** John HJ Petrini
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $949,600
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10221003

## Citation

> US National Institutes of Health, RePORTER application 10221003, DNA Damage & DNA Replication: a Complex Relationship (5R35GM136278-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10221003. Licensed CC0.

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