Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Biochemistry and Biophysics, Penn Center for Genome Integrity, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Trends Biochem Sci. 2021 Sep;46(9):744-757. doi: 10.1016/j.tibs.2021.01.014. Epub 2021 Mar 3.
Poly(ADP-ribosyl) polymerase-1 (PARP-1) is an abundant ADP-ribosyl transferase that regulates various biological processes. PARP-1 is widely recognized as a first-line responder molecule in DNA damage response (DDR). Here, we review the full cycle of detecting DNA damage by PARP-1, PARP-1 activation upon DNA binding, and PARP-1 release from a DNA break. We also discuss the allosteric consequence upon binding of PARP inhibitors (PARPi) and the opportunity to tune its release from a DNA break. It is now possible to harness this new understanding to design novel PARPi for treating diseases where cell toxicity caused by PARP-1 'trapping' on DNA is either the desired consequence or entirely counterproductive.
聚（ADP-核糖）聚合酶 1（PARP-1）是一种丰富的 ADP-核糖基转移酶，可调节多种生物学过程。PARP-1 被广泛认为是 DNA 损伤反应（DDR）中的一线响应分子。在这里，我们回顾了 PARP-1 检测 DNA 损伤的全过程、PARP-1 在 DNA 结合时的激活以及 PARP-1 从 DNA 断裂处的释放。我们还讨论了 PARP 抑制剂（PARPi）结合后的变构后果，以及调节其从 DNA 断裂处释放的机会。现在，我们可以利用这一新的认识来设计新型的 PARPi，以治疗因 PARP-1 在 DNA 上“捕获”而导致细胞毒性的疾病，这种毒性既可以是期望的结果，也可以完全适得其反。
