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Published on: January 31, 2018
FANCJ/BACH1 acetylation at lysine 1249 regulates the DNA damage response
Jenny Xie1, Min Peng, Shawna Guillemette
1Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Abstract:
BRCA1 promotes DNA repair through interactions with multiple proteins, including CtIP and FANCJ (also known as BRIP1/BACH1). While CtIP facilitates DNA end resection when de-acetylated, the function of FANCJ in repair processing is less well defined. Here, we report that FANCJ is also acetylated. Preventing FANCJ acetylation at lysine 1249 does not interfere with the ability of cells to survive DNA interstrand crosslinks (ICLs). However, resistance is achieved with reduced reliance on recombination. Mechanistically, FANCJ acetylation facilitates DNA end processing required for repair and checkpoint signaling. This conclusion was based on the finding that FANCJ and its acetylation were required for robust RPA foci formation, RPA phosphorylation, and Rad51 foci formation in response to camptothecin (CPT). Furthermore, both preventing and mimicking FANCJ acetylation at lysine 1249 disrupts FANCJ function in checkpoint maintenance. Thus, we propose that the dynamic regulation of FANCJ acetylation is critical for robust DNA damage response, recombination-based processing, and ultimately checkpoint maintenance.
Insights
FANCJ acetylation regulates DNA repair. Preventing this modification aids survival of DNA interstrand crosslinks (ICLs) by reducing reliance on recombination, impacting DNA damage response and checkpoint maintenance.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- BRCA1 is crucial for DNA repair, interacting with proteins like CtIP and FANCJ (BRIP1/BACH1).
- CtIP's role in DNA end resection is linked to de-acetylation, but FANCJ's repair function remains less understood.
Purpose of the Study:
- To investigate the role of FANCJ acetylation in DNA repair pathways.
- To elucidate the functional consequences of FANCJ acetylation at lysine 1249 on DNA damage response and checkpoint signaling.
Main Methods:
- Cellular survival assays following DNA interstrand crosslink (ICL) exposure.
- Analysis of DNA repair protein foci formation (RPA, Rad51) after camptothecin (CPT) treatment.
- Assessment of FANCJ acetylation status and its impact on checkpoint maintenance.
Main Results:
- Preventing FANCJ acetylation at K1249 did not impair cell survival after ICLs but reduced reliance on homologous recombination.
- FANCJ acetylation was essential for robust RPA and Rad51 foci formation, indicating its role in DNA end processing.
- Both inhibition and mimicry of FANCJ acetylation at K1249 disrupted checkpoint maintenance.
Conclusions:
- Dynamic regulation of FANCJ acetylation is critical for efficient DNA damage response.
- Acetylation of FANCJ facilitates DNA end processing and is required for proper checkpoint signaling.
- Modulating FANCJ acetylation impacts recombination-based repair and overall genomic stability.
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