Phosphorylation of TIP60 Suppresses 53BP1 Localization at DNA Damage Sites

ABSTRACT

A proper balance between the repair of DNA double-strand breaks (DSBs) by homologous recombination and nonhomologous end joining is critical for maintaining genome integrity and preventing tumorigenesis. This balance is regulated and fine-tuned by a variety of factors, including cell cycle and the chromatin environment. The histone acetyltransferase TIP60 was previously shown to suppress pathological end joining and promote homologous recombination. However, it is unknown how regulatory posttranslational modifications impact TIP60 acetyltransferase activity to influence the outcome of DSB responses. In this study, we report that phosphorylation of TIP60 on serines 90 and 86 is important for limiting the accumulation of the pro-end joining factor 53BP1 at DSBs in S and G₂ cell cycle phases. Mutation of these sites disrupts histone acetylation changes in response to DNA damage, BRCA1 localization to DSBs, and poly(ADP-ribose) polymerase (PARP) inhibitor resistance. These findings reveal that phosphorylation directs TIP60-dependent acetylation to promote homologous recombination and maintain genome stability.

KEYWORDS:

• 53BP1
• BRCA1
• DNA repair
• homologous recombination
• TIP60
• acetylation

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Article of Significant Interest in This Issue

ACKNOWLEDGMENTS

We thank members of the Greenberg lab for critical discussion, John Lough (Medical College of Wisconsin) for providing the Tip60 f/f mice, Eric Brown (University of Pennsylvania) for the Cre-ERT2 mice, and Brendan Price (Dana-Farber Cancer Institute) for TIP60 wild-type and HD mutant constructs.

This work was supported by National Institutes of Health grant R01-CA17494 and funds from the Basser Center for BRCA to R.A.G. M.L.L. was supported by NIH grants T32GM007170 and F30CA196115 and a Patel Scholars Award. B.A.G. acknowledges National Institutes of Health grants P01-GM110174 and P01-CA196539.

We declare that we have no conflicts of interest.