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<p>Precise control of transcription is essential for cell survival under stress conditions, including DNA damage. While mechanisms of DNA damage-induced transcriptional silencing are well characterized, how transcription resumes remains less understood. Here we identify a new role for poly(ADP-ribose) polymerase 1 (PARP1) in transcriptional restart during the DNA damage response (DDR) through a mechanism termed poly(ADP-ribose)-mediated stabilization (PARSTA) of AFF1. Upon DNA damage, PARP1 binds to and PARylates AFF1 in a region targeted by the E3 ligase Siah1, preventing AFF1 ubiquitination and promoting its stability. This stabilization supports efficient transcriptional recovery after DNA damage. Notably, cells resistant to genotoxic stress exhibit elevated PARP1 activity and AFF1 levels, while AFF1 depletion impairs DNA repair and survival. Together, these findings expand PARP1’s role to the transcriptional recovery phase in DDR and suggest that targeting the PARSTA pathway may offer therapeutic potential in diseases characterized by hyperactive PARP1 and elevated levels of AFF1.</p><p></p>

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Stabilization of AFF1 by PARylation ensures transcriptional restart after DNA damage

  • 期刊论文

  • 发表日期：

    2025年10月8日

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  • Feifeng Zhu,
  • Huanyi Fu,
  • Wenxuan Zhu,
  • Chengyu Li,
  • Min Yang,
  • Zeming Feng,
  • Yangqing Shao,
  • Zhuo Li,
  • Yafei Guo,
  • Mengting Huang,
  • Yitong Zhang,
  • Yaohui He,
  • Yi Lu,
  • Zhibing Wu,
  • Qiang Zhou,
  • Huipeng Jiao,
  • Jun Huang,
  • Long Zhang,
  • Yuhua Xue,
  • Huasong Lu

摘要

Precise control of transcription is essential for cell survival under stress conditions, including DNA damage. While mechanisms of DNA damage-induced transcriptional silencing are well characterized, how transcription resumes remains less understood. Here we identify a new role for poly(ADP-ribose) polymerase 1 (PARP1) in transcriptional restart during the DNA damage response (DDR) through a mechanism termed poly(ADP-ribose)-mediated stabilization (PARSTA) of AFF1. Upon DNA damage, PARP1 binds to and PARylates AFF1 in a region targeted by the E3 ligase Siah1, preventing AFF1 ubiquitination and promoting its stability. This stabilization supports efficient transcriptional recovery after DNA damage. Notably, cells resistant to genotoxic stress exhibit elevated PARP1 activity and AFF1 levels, while AFF1 depletion impairs DNA repair and survival. Together, these findings expand PARP1’s role to the transcriptional recovery phase in DDR and suggest that targeting the PARSTA pathway may offer therapeutic potential in diseases characterized by hyperactive PARP1 and elevated levels of AFF1.