Back to search

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Establishing the HPF1/PARP1 complex as a potent cancer drug target

Alternative title: Etablering av HPF1/PARP1-komplekset som et potent kreftmedisinmål

Awarded: NOK 3.9 mill.

The DNA in our cells is under constant attack and thousands of DNA damage sites are generated every second. Damaged DNA needs to be repaired to prevent the development of cancer and other diseases. To combat this assault the cells in our body have a multitude of DNA repair proteins that continuously scan for sites of DNA damage and quickly repair them. If the DNA cannot be repaired these proteins initiates a signal cascade telling the cell to kill itself, known as apoptosis or programmed cell death. Mutations in DNA repair proteins increase cancer susceptibility. Nevertheless, cancer cells with DNA repair defects are dependent on residual repair capacity for survival. A fact that has led to the development of inhibitors against DNA repair proteins. These inhibitors kill cancer cells whereas normal cells survives as they harbour other functional DNA repair pathways. The Poly (ADP-ribose) polymerase 1 (PARP1) protein is a first responder to DNA damage, when PARP1 detects DNA damage it modifies itself and other proteins with a polymer of ADP-ribose. These polymers functions as an emergency signal leading to the recruitment of other DNA repair proteins. Inhibitors against PARP1 have been successful and several have been approved by the FDA. However, 40%-70% of patients fail to respond to treatment and others rapidly develop resistance highlighting the need for new inhibitors. Recently, histone PARylation factor 1 (HPF1) was discovered as an PARP1 interaction partner that is essential for DNA repair. Together these proteins form a composite active site, in which HPF1 provides the critical catalytic amino acid. This discovery opens the possibility of elucidating the molecular basis of PARP1 regulation and developing novel and improved inhibitors. The project will provide the framework for development of new inhibitors by deciphering the reaction mechanism of the HPF1/PARP1 complex and by revealing the role HPF1 plays during treatment with canonical PARP1 inhibitors.

The stability and maintenance of our genome is vital for normal cell division, tissue homeostasis and overall organismal fitness. Chromosomal replication and segregation are processes that are under constant surveillance to ensure fidelity. The DNA damage response (DDR) machinery accurately and efficiently copes with both endogenous and exogenous insults against our genome, and mutations in DNA repair factors increase cancer susceptibility. Nevertheless, cancer cells with DNA repair deficiencies are dependent on residual DDR capacity for survival, a fact that has led to the development of several DNA repair enzyme inhibitors. Inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP1) have been extremely successful and several drugs of this class have been approved by the FDA. Although cancers with BRCA 1/2 mutations are the most sensitive to PARP1 inhibition, 40%-70% of patients in this cohort will fail to respond to treatment and others rapidly develop resistance highlighting the need for new and better inhibitors. The recent discovery of histone PARylation factor 1 (HPF1), a PARP1 specificity factor that is essential for DDR, opens up the possibility of elucidating the molecular basis of PARP1 regulation and developing novel and improved inhibitors. The proposed project will provide the framework for development of new inhibitors by deciphering the reaction mechanism of the HPF1/PARP1 complex and by revealing the role HPF1 plays during treatment with canonical PARP1 inhibitors.

Publications from Cristin

No publications found

No publications found

No publications found

No publications found

Activity:

FRIMEDBIO-Fri prosj.st. med.,helse,biol