Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumourigenesis in mice

Abstract

The DNA strand break-binding molecule, poly(ADPribose) polymerase-1 (PARP-1), plays a role in DNA repair, chromosomal stability, transcription and cell death. Accumulating evidence suggests that dysfunction of PARP-1 contributes to tumorigenesis. Here, we report that PARP-1 deficiency causes mammary carcinoma formation in female mice, and that the introduction of Trp53 mutations accelerates the onset and shortens the latency of mammary tumorigenesis. We show that PARP-1 deficiency results in chromosomal aneuploidy and centrosome amplification, which are substantiated by the inactivation of Trp53 in primary mammary epithelial (PME) cells. In addition, PARP-1 deficiency compromises p53 activation and impairs BRCA1 recruitment to the sites of DNA damage in PME cells. PARP-1 complementation partly rescues the defective DNA damage response mediated by p53 and BRCA1. The present study thus identifies a role of PARP-1 in suppressing mammary tumorigenesis in vivo and suggests that dysfunction of PARP-1 may be a risk factor for breast cancer in humans.

Loss of poly(ADP-ribose) polymerase-2 leads to rapid development of spontaneous T-cell lymphomas in p53-deficient mice

“…These data suggest a synergistic interaction between Parp-2 and p53 in the maintenance of genome integrity, resulting in accelerated tumorigenesis when both genes are disrupted in mice (Figure 3b). Parp-1 deficiency has also been shown to shorten the latency of tumour development in p53 À/À mice (Beneke and Mo¨ro¨y, 2001;Tong et al, 2001Tong et al, , 2003Tong et al, , 2007. However, Parp-1 deficiency in mice, in contrast to Parp-2 deficiency, did not affect either thymocyte development (Yelamos et al, 2006) or thymocyte apoptosis in response to different stimuli (Wang et al, 1997).…”

“…Among the 17 members of the Parp family, Parp-1 (113 kDa) and Parp-2 (62 kDa) are so far the only Parp enzymes whose catalytic activity has been shown to be stimulated by DNA strand interruptions, targeting proteins mainly involved in chromatin structure and DNA metabolism Yelamos et al, 2008). Whereas Parp-1-deficient (Parp-1 À/À ) mice develop spontaneous mammary and liver tumours with long latency and at a low incidence (Tong et al, 2002(Tong et al, , 2007, Parp-2 À/À mice do not show the propensity for development of spontaneous tumours (Menissier et al, 2003). However, both Parp-1 À/À mice and Parp-2 À/À mice are very sensitive to ionizing radiation and alkylating agents, thus suggesting a role for these proteins in the cellular response to DNA damage and genomic stability through their physical association with, or by the poly(ADPribosyl)ation of their partner proteins (Menissier et al, 2003).…”

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

“…Some phenanthrene-derived poly-ADP-ribose polymerase (PARP) inhibitors also exhibit cancer cell-specific declustering. 134 PARP-1 expression is upregulated in various human cancers 135 but downregulated in others, 136 suggesting a complex role for this protein in tumorigenesis. Treatment of tumors exhibiting centrosome amplification with the phenanthrene-derived PARP-1 inhibitor, PJ-34, results in clustering inhibition, spindle multipolarity, and death by mitotic catastrophe.…”

“…However, PARP-1 has been implicated in centrosome amplification. 136 Furthermore, in their screen for clustering proteins in S2 cells, Kwon et al 6 identified a PARP, tankyrase-1, and a putative PARP-16 homolog as molecules critical for clustering. Considering that PARP-1 inhibitors induce declustering, these drugs evince great potential for cancer cell-specific chemotherapy.…”

BRCA2 Mutations and Consequences for DNA Repair

“…And, the potential for secondary cancers to occur through genomic instability from inhibition of PARP-1 is possible. In an in vivo study of PARP-1 deficiency, female mice developed mammary carcinoma (Tong, Yang et al 2007); (Drew and Plummer). Furthermore, secondary mutations after PARP inhibitor treatment may lead to drug resistance.…”