The FANCJ/MutLα interaction is required for correction of the cross‐link response in FA‐J cells
Open accessAbstract
FANCJ also called BACH1/BRIP1 was first linked to hereditary breast cancer through its direct interaction with BRCA1. FANCJ was also recently identified as a Fanconi anemia (FA) gene product, establishing FANCJ as an essential tumor suppressor. Similar to other FA cells, FANCJ-null (FA-J) cells accumulate 4N DNA content in response to DNA interstrand crosslinks (ICLs). This accumulation is corrected by reintroduction of wild-type FANCJ. Here, we show that FANCJ interacts with the mismatch repair complex MutLalpha, composed of PMS2 and MLH1. Specifically, FANCJ directly interacts with MLH1 independent of BRCA1, through its helicase domain. Genetic studies reveal that FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation and sensitivity to ICLs. These results suggest that the FANCJ/MutLalpha interaction, but not FANCJ/BRCA1 interaction, is essential for establishment of a normal ICL-induced response. The functional role of the FANCJ/MutLalpha complex demonstrates a novel link between FA and MMR, and predicts a broader role for FANCJ in DNA damage signaling independent of BRCA1.
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Experiments using FANCJ-null FA-J patient cells complemented with K52R or A349P demonstrated that FANCJ enzyme activity and the Fe-S domain are essential for DNA interstrand crosslink repair.
“Experiments using FANCJ-null FA-J patient cells complemented with K52R or the A349P FA-associated mutant demonstrated that FANCJ enzyme activity and the Fe–S domain are essential for DNA interstrand crosslink repair [42,73].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [73]
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References 48 · Cited by 181
- Authors
- Peng, M., Litman, R., Xie, J., Sharma, S., Brosh, R. M., & Cantor, S. B.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- National Institutes of Health (US)
- Corresponding author
- Cantor, Sharon B
- Venue
- The EMBO Journal
- Published
- 2007-06-21
- Volume
- 26
- Issue
- 13
- Pages
- 3238-3249
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1914102
- OpenAlex
- W2166483233
- Cited by
- 181
- References
- 48
- Citations by year
- 2026: 7 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 11 · 2019: 3 · 2018: 6 · 2017: 5 · 2016: 11 · 2015: 9 · 2014: 12 · 2013: 11 · 2012: 9
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- eScholarship@UMassChan (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Keywords
- FANCJ, BRIP1, MutLα, MLH1, PMS2, interstrand cross-links, Fanconi anemia, DNA mismatch repair, DNA helicase activity, BRCA1, DNA damage response, tumor suppressor
- MeSH terms
- MutL Proteins, MutL Protein Homolog 1, Mismatch Repair Endonuclease PMS2, Adenosine Triphosphatases, Cell Line, DNA, DNA-Binding Proteins, Fanconi Anemia, Gene Expression Regulation, Lysine, Nuclear Proteins, Protein Binding, Sensitivity and Specificity, Ubiquitin, DNA Repair Enzymes, Adaptor Proteins, Signal Transducing, Basic-Leucine Zipper Transcription Factors, Fanconi Anemia Complementation Group Proteins, Fanconi Anemia Complementation Group D2 Protein
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