PARP-1 and its associated nucleases in DNA damage response

Abstract

Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) acts as a DNA damage sensor. It recognizes DNA damage and facilitates DNA repair by recruiting DNA repair machinery to damage sites. Recent studies reported that PARP-1 also plays an important role in DNA replication by recognizing the unligated Okazaki fragments and controlling the speed of fork elongation. On the other hand, emerging evidence reveals that excessive activation of PARP-1 causes chromatin DNA fragmentation and triggers an intrinsic PARP-1-dependent cell death program designated parthanatos, which can be blocked by genetic deletion or pharmacological inhibition of PARP-1. Therefore, PARP-1 plays an essential role in maintaining genomic stability by either facilitating DNA repair/replication or triggering DNA fragmentation to kill cells. A group of structure-specific nucleases is crucial for executing DNA incision and fragmentation following PARP-1 activation. In this review, we will discuss how PARP-1 coordinates with its associated nucleases to maintain genomic integrity and control the decision of cell life and death.

Keywords: Cell death; DNA damage; DNA replication/repair; Nuclease; PARP-1.

Figure 1.. PARP-1 cooperates with nucleases and controls genomic stability.

Upon DNA damage induced by oxidative stress or alkylating agents abundant in the environment, PARP-1 is activated to synthesize PAR. As a consequence, specific nucleases are recruited to DNA damage sites to either facilitate DNA damage repair/replication, or trigger DNA degradation leading to cell death. Me, methylation; OH, hydroxylation.

Figure 2.. MIF is the executor for PARP-1 dependent cell death (parthanatos).

Stresses induce DNA damage, PARP1 activation, and subsequently PAR formation. PAR facilitates the release of AIF from mitochondria. AIF recruits MIF to the nucleus, where MIF cleaves genomic DNA into large DNA fragments and causes cell death. Interference with this cascade by blocking either the formation of the AIF-MIF complex or MIF nuclease activity prevents DNA fragmentation and promotes cell survival.

Figure 3.. MIF is a novel Mg²⁺/Ca²⁺-dependent 3’ exonuclease.

MIF trimer specifically recognizes the ssDNA with a stem loop structure as the substrate. It binds to the 5’ unpaired region of stem loop structured ssDNA, but selectively cleaves at its 3’ unpaired ssDNA.

Figure 4.. The model of context-dependent functions of PARP-1 and nucleases in DNA repair and cell death.

The role of PARP-1 is highly context-dependent in response to different types of DNA damage in different types of cells and tissues. In BRCA1/2-deficient cancer cells, PARP-1 plays a critical role in DNA damage repair. PARP-1 inhibitors combined with DNA damage chemotherapy drugs kill cancer cells. However, in BRCA1/2-proficient cells, DNA alkylating agents or oxidative stress may cause PARP-1 hyperactivation, PAR accumulation and DNA degradation leading to cell death. Inhibition of PARP-1 prevents cell death. A group of structure-specific nucleases is recruited by activated PARP-1 in response to DNA damage. Future studies are required to understand if these PARP-1-associated nucleases execute different functions under the different contexts.