MacroH2A1 Regulation of Poly(ADP-Ribose) Synthesis and Stability Prevents Necrosis and Promotes DNA Repair.

Penelope D Ruiz,Jong Woo Park,Gregory A Hamilton,Matthew J Gamble

doi:10.1128/mcb.00230-19

Penelope D Ruiz, Jong Woo Park + Show 2 more

Open Access

https://doi.org/10.1128/mcb.00230-19

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Abstract

Through its ability to bind the ends of poly(ADP-ribose) (PAR) chains, the function of the histone variant macroH2A1.1, including its ability to regulate transcription, is coupled to PAR polymerases (PARPs). PARP1 also has a major role in DNA damage response (DDR) signaling, and our results show that macroH2A1 alters the kinetics of PAR accumulation following acute DNA damage by both suppressing PARP activity and simultaneously protecting PAR chains from degradation. In this way, we demonstrate that macroH2A1 prevents cellular NAD+ depletion, subsequently preventing necrotic cell death that would otherwise occur due to PARP overactivation. We also show that macroH2A1-dependent PAR stabilization promotes efficient repair of oxidative DNA damage. While the role of PAR in recruiting and regulating macrodomain-containing proteins has been established, our results demonstrate that, conversely, macrodomain-containing proteins, and specifically those containing macroH2A1, can regulate PARP1 function through a novel mechanism that promotes both survival and efficient repair during DNA damage response.

Highlights

Through its ability to bind the ends of poly(ADP-ribose) (PAR) chains, the function of the histone variant macroH2A1.1, including its ability to regulate transcription, is coupled to PAR polymerases (PARPs)
Given the ability of macroH2A1.1 to interact with PAR, we evaluated the role of PARP activity in mediating the increased necrosis in response to oxidative DNA damage in the macroH2A1-depleted cells
Phosphorylation of H2AX triggers the recruitment of repair factors to sites of DNA double-strand breaks [56]

Summary

Introduction

Through its ability to bind the ends of poly(ADP-ribose) (PAR) chains, the function of the histone variant macroH2A1.1, including its ability to regulate transcription, is coupled to PAR polymerases (PARPs). PARP1 has a major role in DNA damage response (DDR) signaling, and our results show that macroH2A1 alters the kinetics of PAR accumulation following acute DNA damage by both suppressing PARP activity and simultaneously protecting PAR chains from degradation. In this way, we demonstrate that macroH2A1 prevents cellular NADϩ depletion, subsequently preventing necrotic cell death that would otherwise occur due to PARP overactivation. PAR chains have roles in multiple repair pathways, including both longand short-patch base excision repair (BER), single-strand break repair (SSBR), DSB repair, and the removal of bulky adducts [7] In this way, PARP1 can promote cellular survival during a DNA damage response. The ability of ALC1 to remodel nucleosomes requires its interaction with PAR [15]

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