PARP1 regulates the protein stability and proapoptotic function of HIPK2

Abstract

Homeodomain-interacting protein kinase 2 (HIPK2) is a nuclear serine/threonine kinase that functions in DNA damage response and development. In the present study, we propose that the protein stability and proapoptotic function of HIPK2 are regulated by poly(ADP-ribose) polymerase 1 (PARP1). We present evidence indicating that PARP1 promotes the proteasomal degradation of HIPK2. The tryptophan-glycine-arginine (WGR) domain of PARP1 was necessary and sufficient for the promotion of HIPK2 degradation independently of the PARP1 enzymatic activity. The WGR domain mediated the interaction between HIPK2 and C-terminus of HSP70-interacting protein (CHIP) via HSP70. We found that CHIP can function as a ubiquitin ligase for HIPK2. The interaction between PAPR1 and HIPK2 was weakened following DNA damage. Importantly, PARP1 reduced the HIPK2-mediated p53 phosphorylation, proapoptotic transcriptional activity and cell death. These results suggest that PARP1 can modulate the tumor-suppressing function of HIPK2 by regulating the protein stability of HIPK2.

Hyperglycemia triggers HIPK2 protein degradation

“…As apoptosis alteration is responsible, among other effects, of tumor resistance to therapies [ 40 ], the regulation of HIPK2 expression level and activity is of particular relevance for the determination of cell fate between survival and death. Previous studies established that HIPK2 protein stability is tightly regulated by ubiquitin-proteasome system [ 12 – 14 , 20 – 22 , 32 , 41 ]. In the present study, we have shown that hyperglycemia promotes the degradation of HIPK2 in parte through ubiquitin ligase Siah2 downstream of a protein cascade including PP2A and HIF-1α, as summarized in the scheme (Figure 6 ).…”

“…As previous studies established that HIPK2 protein stability is tightly regulated by several ubiquitin ligases acting in different cellular conditions [ 12 – 14 , 20 – 22 , 32 , 41 ], we asked what was the link between HG, PP2A and HIPK2 stability. Data from the literature reported that PP2A activation, upon increased glucose flux, induces carbohydrate response element binding protein (ChREBP) dephosphorylation and nuclear translocation to bind to the proximal HIF1A promoter, stimulating its transcription and HIF-1α stabilization even in normoxic condition [ 26 , 52 – 54 ] (Figure 6 ).…”

The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma

“…With low-level of DNA damage, PARP1 promotes cell survival by repairing SSBs of DNA and does not permit their progression to toxic double-strand breaks (DSBs) of DNA [ 5 ]. If SSBs of DNA progress to DSBs, PARP1 induces phosphorylation of H2AX (γH2AX) and induces recruitment of BRCA1/2 to repair DSBs, which eventually prevents apoptotic cell death [ 6 , 7 ]. Therefore, PARP1 has a vital role in the survival of damaged cells, and could confer a survival advantage to cancer cells during anti-cancer therapy targeting apoptosis of cancer cells [ 8 ].…”

“…When there are defects in BRCA1/2, inhibition of PARP1 induces accumulation of SSBs which eventually progresses to DSBs that lead to apoptosis [ 4 , 10 , 11 ]. In this context, PARP inhibitors might be promising anticancer drugs in conjunction with DNA repair deficits [ 3 , 4 , 6 , 7 , 12 ]. Therapeutic efficacy of PARP inhibition has been proposed for human papilloma virus-related squamous cell carcinomas and colorectal carcinomas [ 13 , 14 ].…”

A novel predicted ADP-ribosyltransferase family conserved in eukaryotic evolution

“…The members of the poly-ADP-ribosyltransferase (PARP) family, PARP1 and PARP2, are examples of ARTs that modify proteins interacting with DNA. PARP1 and PARP2 are localized in the nucleus where they are involved in many cellular processes [29][30][31][32]. PARP1 and PARP2 transferase activity is known to be necessary for repair of DNA damage such as deamination, hydroxylation and methylation of nitrogenous bases as well as for repair of single strand breaks.…”