FANCJ/BACH1 Acetylation at Lysine 1249 Regulates the DNA Damage Response

Jenny Xie,Steven Quan,Scott A Shaffer,Yuliang Wu,Stephanie Maniatis,Robert M Brosh,Min Peng,Shawna Guillemette,Aditya Venkatesh,Sharon B Cantor,Sharon E Plon

doi:10.1371/journal.pgen.1002786

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.

Highlights

The hereditary breast cancer associated gene product, BRCA1 is an essential tumor suppressor
Given that CtIP function is inactivated by acetylation [16], we addressed whether FANCJ was modified
In an immunoblot probed with a pan-acetyl lysine antibody, we found that the precipitated FANCJ was acetylated only when CBP was over-expressed (Figure 1A)

Summary

Introduction

The hereditary breast cancer associated gene product, BRCA1 is an essential tumor suppressor. Through its C-terminal BRCT repeats, BRCA1 directly interacts with Abraxas, CtIP and FANCJ ( known as BRIP1 or BACH1 (BRCA1-associated C-terminal helicase 1)). These BRCT-interacting proteins contribute to the function of BRCA1 in the DNA damage response (DDR). Abraxas serves to localize BRCA1 to sites of DNA damage and CtIP promotes the initiation of DNA end resection, which is critical for HR [1,2,3]. FANCJ participates in localizing BRCA1 to sites of DNA damage, in DNA repair, and in checkpoint signaling; its distinct function is less clear

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Conclusion