# ATR Isomerization in Cellular Responses to UV Damage of DNA

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2021 · $353,417

## Abstract

Summary
 DNA damage is a major cause of human cancers and many other human diseases. In response to
DNA damage, cells activate DNA damage response (DDR) pathways such as DNA damage checkpoints,
DNA repair, and apoptosis. ATR (ataxia telangiectasia and Rad3-related), a member of the
phosphoinositide 3-kinase-related protein kinases (PIKK) family, is a major DNA damage checkpoint
protein kinase which plays a critical role in DDR by signaling DNA damage, activating checkpoints,
arresting cell cycle progression and facilitating DNA repair to restore DNA integrity. Interestingly, a body
of evidence from mouse model and human epidemiologic studies shows that unlike ATM, a closely related
ATR-like PIKK family member whose deficiency promotes carcinogenesis, ATR inhibition suppresses
carcinogenesis. Moreover, ATR knockout is embryonically lethal. These suggest an involvement of ATR
in regulating cell death. Although ATR has been extensively studied as a checkpoint kinase in DDR in the
nucleus, little is known about its functions in the cytoplasm or mitochondria, the cellular organelle for
activating DNA damage-induced apoptosis. A recent finding from the P.I.’s lab reveals that (a) besides its
hallmark nuclear checkpoint functions, ATR is a pro-survival protein functioning directly at mitochondria
against UV damage; (b) ATR contains a BH3-like domain that allows ATR to act like a Bcl-2 family protein;
(c) importantly, mitochondrial ATR is a prolyl cis-isomeric form of ATR regulated by Pin1 while in contrast,
nuclear ATR is a trans-isomeric form of ATR; and finally (d) mitochondria activity of ATR is independent of
its checkpoint kinase activity and ATRIP. In this project, we will test the hypotheses that (1) Prolyl
isomerization alters the structure of ATR, transforming ATR functions for mitochondria-specific activities to
promote cell survival or nuclear functions as a DNA damage checkpoint regulator; (2) Antiapoptotic activity
of ATR at mitochondria plays an important role in mediating carcinogenesis in vivo, and thus, suppressing
such activity may reduce carcinogenesis/tumorigenesis and provide a strategy for cancer prevention and
treatment; and (3) ATR’s trans-isomeric form is required for its DNA damage checkpoint activity, and post-
translational modifications of ATR and/or ATR-ATRIP complex formation may play a role in stabilizing ATR
in the trans-isomeric form in the nucleus. These hypotheses will be tested in the following specific aims.
Aim 1: To define the structure-function relationships of ATR prolyl isomers, and of ATRH-tBid and ATRH-
Pin1 interactions; Aim 2: To determine the role of prolyl isomerization in the nuclear functions of ATR; and
Aim 3: To determine the in vivo effects of ATR isomers on carcinogenesis and tumorigenesis. The
proposed studies represent an innovative effort highly relevant to cancer biology and also having
implications in other human diseases such as neurodegenerative and cardiovascular diseases.

## Key facts

- **NIH application ID:** 10220898
- **Project number:** 5R01CA219342-05
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Yue Zou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,417
- **Award type:** 5
- **Project period:** 2017-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220898

## Citation

> US National Institutes of Health, RePORTER application 10220898, ATR Isomerization in Cellular Responses to UV Damage of DNA (5R01CA219342-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220898. Licensed CC0.

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