A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors

Lior Izhar, Britt Adamson, Alberto Ciccia, Jedd Lewis, Laura Pontano-Vaites, Yumei Leng, Anthony C. Liang, Thomas F. Westbrook, J. Wade Harper, Stephen J. Elledge

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Localization to sites of DNA damage is a hallmark of DNA damage response (DDR) proteins. To identify DDR factors, we screened epitope-tagged proteins for localization to sites of chromatin damaged by UV laser microirradiation and found >120 proteins that localize to damaged chromatin. These include the BAF tumor suppressor complex and the amyotrophic lateral sclerosis (ALS) candidate protein TAF15. TAF15 contains multiple domains that bind damaged chromatin in a poly-(ADP-ribose) polymerase (PARP)-dependent manner, suggesting a possible role as glue that tethers multiple PAR chains together. Many positives were transcription factors; > 70% of randomly tested transcription factors localized to sites of DNA damage, and of these, ~90% were PARP dependent for localization. Mutational analyses showed that localization to damaged chromatin is DNA-binding-domain dependent. By examining Hoechst staining patterns at damage sites, we see evidence of chromatin decompaction that is PARP dependent. We propose that PARP-regulated chromatin remodeling at sites of damage allows transient accessibility of DNA-binding proteins. Localization to sites of DNA damage is a hallmark of DNA damage response proteins. Izhar et al. identify >120 proteins that localize to damaged chromatin including the BAF tumor suppressor complex and the ALS candidate protein TAF15. Many positives were transcription factors that localize to sites of DNA damage in a PARP-dependent manner. They provide evidence of chromatin decompaction that is PARP dependent and propose that PARP-regulated chromatin remodeling at damage sites allows accessibility of DNA-binding proteins and other factors.

Original languageEnglish (US)
Pages (from-to)1486-1500
Number of pages15
JournalCell Reports
Volume11
Issue number9
DOIs
StatePublished - Jun 9 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Izhar, L., Adamson, B., Ciccia, A., Lewis, J., Pontano-Vaites, L., Leng, Y., Liang, A. C., Westbrook, T. F., Harper, J. W., & Elledge, S. J. (2015). A Systematic Analysis of Factors Localized to Damaged Chromatin Reveals PARP-Dependent Recruitment of Transcription Factors. Cell Reports, 11(9), 1486-1500. https://doi.org/10.1016/j.celrep.2015.04.053