It takes two to tango: PARP1 active site is completed by HPF1

It takes two to tango: PARP1 active site is completed by HPF1

PARP1 is a poly [ADP-ribose] polymerase that can sense DNA damage and facilitate the choice of repair pathway. Currently, PARP1 inhibitors are the preferred treatment for carcinomas which are already deficient in DNA damage repair through acquired BRCA1/2 mutations.

In their previous work, Ivan Ahel group showed that the PARP1 inhibitor efficacy is greatly increased in cells lacking HPF1, a PARP1 interacting protein. In cells, PARP1 preferentially adds poly ADP-ribose to serine residues of proteins, while in vitro PARP1 modifies aspartate and glutamate residues. Strikingly, adding HPF1 to an in vitro reaction corrected PARP1 specificity to serine. Therefore, the group concluded that HPF1 likely plays a crucial part in PARP1 function.

In a recent publication from Ivan Ahel lab, Marcin Suskiewicz, Florian Zobel, and colleagues show that HPF1 directly contributes to the PARP1 active site with substrate binding and catalytic residues. The strong HPF1-PARP1 interaction is opposed by an autoinhibitory region of PARP1. This region is known to locally unfold on binding DNA lesions. Therefore, the authors propose that the complex formation is a regulatory mechanism restricting PARP1 activity until suitable cues, such as DNA damage induced PARP1 DNA binding, present themselves. This work hugely contributed to our mechanistic understanding of ADP-ribosylation synthesis and reversal. Most importantly, the authors provided the clinical community with an important puzzle piece that could help explain and predict reactions to PARP1 inhibitors.

Lucie Kafkova

Suskiewicz MJ, Zobel F, Ogden TEH, Fontana P, Ariza A, Yang JC, Zhu K, Bracken L, Hawthorne WJ, Ahel D, Neuhaus D, Ahel I (2020).