BRCA1 is required for hMLH1 stabilization following doxorubicin-induced DNA damage
Abstract
Human DNA mismatch repair (MMR) is involved in the removal of DNA base mismatches that arise either during DNA replication or are caused by DNA damage. In this study, we show that the activation of the MMR component hMLH1 in response to doxorubicin (DOX) treatment requires the presence of BRCA1 and that this phenomenon is mediated by an ATM/ATR dependent phosphorylation of the hMLH1 Ser-406 residue. BRCA1 is an oncosuppressor protein with a central role in the DNA damage response and it is a critical component of the ATM/ATR mediated checkpoint signaling. Starting from a previous finding in which we demonstrated that hMLH1 is able to bind to BRCA1, in this study we asked whether BRCA1 might be the bridge for ATM/ATR dependent phosphorylation of the hMLH1 molecular partner. We found that: (i) the negative modulation of BRCA1 expression is able to produce a remarkable reversal of hMLH1 stabilization, (ii) BRCA1 is required for post-translational modification produced by DOX treatment on hMLH1 which is, in turn, attributed to the ATM/ATR activity, (iii) the serine 406 phosphorylatable residue is critical for hMLH1 activation by ATM/ATR via BRCA1. Taken together, our data lend support to the hypothesis suggesting an important role of this oncosuppressor as a scaffold or bridging protein in DNA-damage response signaling via downstream phosphorylation of the ATM/ATR substrate hMLH1.
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ATM is essential for MLH1 phosphorylation at serine 406 and its stability after doxorubicin treatment, suggesting that ATM regulates mismatch repair proteins.
“ATM is essential for MLH1 phosphorylation at Serine 406 and its stability following chemotherapy drug doxorubicin treatment, suggesting the regulation of MMR proteins by ATM [173].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [173]
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Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
- Authors
- Romeo, F., Falbo, L., Di Sanzo, M., Misaggi, R., Faniello, M. C., Viglietto, G., Cuda, G., Costanzo, F., & Quaresima, B.
- Affiliations
- Magna Graecia University (IT)
- Corresponding author
- Costanzo, Francesco
- ORCID
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 43
- Issue
- 12
- Pages
- 1754-1763
- ISSN
- 1357-2725 (ISSN-L)
- OpenAlex
- W2072547020
- Cited by
- 18
- References
- 43
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2020: 1 · 2019: 2 · 2018: 2 · 2017: 2 · 2016: 1 · 2014: 2 · 2013: 2
- FWCI
- 0.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Ministero dell'Università e della Ricerca
- 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 › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- BRCA1, MLH1, DNA mismatch repair, doxorubicin, DNA damage response, ATM/ATR signaling, protein phosphorylation, protein stabilization, oncosuppressor, checkpoint signaling
- MeSH terms
- MutL Protein Homolog 1, Antibiotics, Antineoplastic, DNA, DNA Damage, Doxorubicin, Humans, Nuclear Proteins, Phosphorylation, Protein Processing, Post-Translational, Serine, Signal Transduction, BRCA1 Protein, Adaptor Proteins, Signal Transducing
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