Proteomic Analysis of the Downstream Signaling Network of PARP1

Yuanli Zhen, Yonghao Yu

Research output: Contribution to journalReview article

7 Citations (Scopus)

Abstract

Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies. Indeed, three PARP1 inhibitors (Olaparib, Rucaparib, and Niraparib) have recently been approved by the Food and Drug Administration for the treatment of ovarian cancer. Moreover, in 2017, both Olaparib and Niraparib have also been approved for the treatment of fallopian tube cancer and primary peritoneal cancer. Despite this very exciting progress in the clinic, the basic signaling mechanism that connects PARP1 to a diverse array of biological processes is still poorly understood. This is, in large part, due to the inherent technical difficulty associated with the analysis of protein PARylation, which is a low-abundance, labile, and heterogeneous PTM. The study of PARylation has been greatly facilitated by the recent advances in mass spectrometry-based proteomic technologies tailored to the analysis of this modification. In this Perspective, we discuss these breakthroughs, including their technical development, and applications that provide a global view of the many biological processes regulated by this important protein modification.

Original languageEnglish (US)
Pages (from-to)429-440
Number of pages12
JournalBiochemistry
Volume57
Issue number4
DOIs
StatePublished - Jan 30 2018

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Biological Phenomena
Proteomics
Adenosine Diphosphate
Post Translational Protein Processing
Proteins
Fallopian Tube Neoplasms
Poly(ADP-ribose) Polymerases
DNA
United States Food and Drug Administration
Nuclear Proteins
Ovarian Neoplasms
DNA Damage
Mass spectrometry
Mass Spectrometry
Neoplasms
Technology
Enzymes
olaparib
niraparib

ASJC Scopus subject areas

  • Biochemistry

Cite this

Proteomic Analysis of the Downstream Signaling Network of PARP1. / Zhen, Yuanli; Yu, Yonghao.

In: Biochemistry, Vol. 57, No. 4, 30.01.2018, p. 429-440.

Research output: Contribution to journalReview article

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abstract = "Poly-ADP-ribosylation (PARylation) is a protein posttranslational modification (PTM) that is critically involved in many biological processes that are linked to cell stress responses. It is catalyzed by a class of enzymes known as poly-ADP-ribose polymerases (PARPs). In particular, PARP1 is a nuclear protein that is activated upon sensing nicked DNA. Once activated, PARP1 is responsible for the synthesis of a large number of PARylated proteins and initiation of the DNA damage response mechanisms. This observation provided the rationale for developing PARP1 inhibitors for the treatment of human malignancies. Indeed, three PARP1 inhibitors (Olaparib, Rucaparib, and Niraparib) have recently been approved by the Food and Drug Administration for the treatment of ovarian cancer. Moreover, in 2017, both Olaparib and Niraparib have also been approved for the treatment of fallopian tube cancer and primary peritoneal cancer. Despite this very exciting progress in the clinic, the basic signaling mechanism that connects PARP1 to a diverse array of biological processes is still poorly understood. This is, in large part, due to the inherent technical difficulty associated with the analysis of protein PARylation, which is a low-abundance, labile, and heterogeneous PTM. The study of PARylation has been greatly facilitated by the recent advances in mass spectrometry-based proteomic technologies tailored to the analysis of this modification. In this Perspective, we discuss these breakthroughs, including their technical development, and applications that provide a global view of the many biological processes regulated by this important protein modification.",
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