Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress
Open accessAbstract
The BRCA1 gene encodes a tumor suppressor that is mutated in 50% of familial breast cancers. The BRCA1 protein has been implicated in the DNA damage response, as DNA damage induces the phosphorylation of BRCA1 and causes its recruitment into nuclear foci that contain DNA repair proteins. The ataxia-telangiectasia-mutated (ATM) gene product controls overall BRCA1 phosphorylation in response to γ-irradiation (IR). In this study, we show that BRCA1 phosphorylation is only partially ATM dependent in response to IR and ATM independent in response to treatment with UV light, or the DNA replication inhibitors hydroxyurea (HU) and aphidicolin (APH). We provide evidence that the kinase responsible for this phosphorylation is the ATM-related kinase, ATR. ATR phosphorylates BRCA1 on six Ser/Thr residues, including Ser 1423, in vitro. Increased expression of ATR enhanced the phosphorylation of BRCA1 on Ser 1423 following cellular exposure to HU or UV light, whereas doxycycline-induced expression of a kinase-inactive ATR mutant protein inhibited HU- or UV light-induced Ser 1423 phosphorylation in GM847 fibroblasts, and partially suppressed the phosphorylation of this site in response to IR. Thus, ATR, like ATM, controls BRCA1 phosphorylation in vivo. Although ATR isolated from DNA-damaged cells does not show enhanced kinase activity in vitro, we found that ATR responds to DNA damage and replication blocks by forming distinct nuclear foci at the sites of stalled replication forks. Furthermore, ATR nuclear foci overlap with the nuclear foci formed by BRCA1. The dramatic relocalization of ATR in response to DNA damage points to a possible mechanism for its ability to enhance the phosphorylation of substrates in response to DNA damage. Together, these results demonstrate that ATR and BRCA1 are components of the same genotoxic stress-responsive pathway, and that ATR directly phosphorylates BRCA1 in response to damaged DNA or stalled DNA replication.
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H2AX is phosphorylated both in G1 and S phases by ATR in response to UV irradiation.
“H2AX is phosphorylated both in G1 and S phases by ATR in response to UV irradiation [26;32–38].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [34]
ATR is predominantly responsible for the DNA damage response upon UVR exposure.
“Previous studies support that ATR is predominantly responsible for DDR upon UVR exposure”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [34]
Upon UV irradiation and replication fork stalling, replication repair factors such as BRCA1, RAD51 and FANCD2 form nuclear foci.
“Accordingly, upon UV irradiation and replication fork stalling, replication repair factors such as BRCA1, RAD51 and FANCD2 form nuclear foci [34].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [34]
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Multifactorial contributions to an acute DNA damage response by BRCA1/BARD1-containing complexes
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Self-citationATM: Genome stability, neuronal development, and cancer cross paths
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ATR autophosphorylation as a molecular switch for checkpoint activation
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DNA Damage Response: Three Levels of DNA Repair Regulation
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Self-citationRecruitment of Mec1 and Ddc1 Checkpoint Proteins to Double-Strand Breaks Through Distinct Mechanisms
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A Role for Proapoptotic BID in the DNA-Damage Response
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A Murine Model of Nijmegen Breakage Syndrome
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CCDC98 targets BRCA1 to DNA damage sites
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Recruitment of the Cell Cycle Checkpoint Kinase ATR to Chromatin during S-phase
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Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export
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BACH1 is a DNA repair protein supporting BRCA1 damage response
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Aberrant expression of TopBP1 in breast cancer
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- Authors
- Tibbetts, R. S., Cortez, D., Brumbaugh, K. M., Scully, R., Livingston, D., Elledge, S. J., & Abraham, R. T.
- Affiliations
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2000-12-01
- Volume
- 14
- Issue
- 23
- Pages
- 2989-3002
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317107
- OpenAlex
- W2005284058
- Cited by
- 512
- References
- 66
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 4 · 2023: 8 · 2022: 12 · 2021: 13 · 2020: 7 · 2019: 8 · 2018: 11 · 2017: 9 · 2016: 7 · 2015: 16 · 2014: 13 · 2013: 18 · 2012: 12
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- Jane Coffin Childs Memorial Fund for Medical Research
- Wellcome Trust
- National Institutes of Health
- Johnson and Johnson
- National Cancer Institute (CA76193, U01CA052995, CA-52995, R01CA076193, F32CA083319, U19CA052995)
- National Institute of General Medical Sciences (GM-44664, R37GM044664, R01GM044664)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- BRCA1, ATR kinase, ATM, BRCA1 phosphorylation, DNA damage response, genotoxic stress, replication stress, stalled replication forks, nuclear foci, ultraviolet radiation, hydroxyurea, aphidicolin, gamma irradiation, tumor suppressor
- MeSH terms
- Animals, Catalysis, Cell Line, Transformed, Cell Nucleus, DNA Damage, DNA Repair, Humans, Phosphorylation, Rabbits, Serine, Signal Transduction, Gene Expression, Protein Serine-Threonine Kinases, Cell Cycle Proteins, BRCA1 Protein, K562 Cells, Ataxia Telangiectasia Mutated Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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