## 1 Introduction  
The poly-ADP-ribose polymerase (PARP) family consists of 17 enzymes that use nicotinamide adenine dinucleotide (NAD\({}^{+}\)) as a substrate to transfer ADP-ribose onto themselves and target proteins [1, 2]. This activity depends on the conserved histidine-tyrosine-glutamate (HYE) catalytic triad motif, although the glutamate residue is absent in 11 of the protein family members, suggesting that they differ in their catalytic activity [3, 4]. The majority of PARPs catalyze the transfer of one ADP-ribose monomer, a process known as mono-ADP-ribosylation [2 the modification may affect cellular stress responses, DNA repair, immunity, transcription and metabolism [6; 7; 8]. ADP-ribosylation is removed by enzymes such as poly-ADP-ribose polycohydrolases (PARGs), ADP-ribosyl hydrolases (ARHs) and macro domain containing proteins, making the modification reversible [8; 9; 10].  
PARP7 (TIPARP; ARTD14), is a mono-ADP-ribosyltransferase that is a critical regulator of innate immunity, transcription factor activity, and cellular stress responses [11; 12]. PARP7 is expressed in most human tissues, and has an N-terminal nuclear localization signal (NLS), followed by a cysteine-cysteine-cysteine-histidine (CCCH)-type zinc finger domain which can bind RNA, a tryptophan-tryptophan-glutamate (WWE) domain which can bind ADP-ribose and mediate protein-protein interactions, and a conserved PARP domain responsible for its enzymatic activity [3; 13; 14; 15; 16]. Expression of PARP7 is regulated by the aryl hydrocarbon receptor (AHR), and PARP7 acts as a repressor of AHR activity via mono-ADP-ribosylation [17]. PARP7 is also regulated by liver X receptors (LXRs) [18], hypoxia-inducible factor 1 (HIF-1\(\alpha\)) [19], and the type I interferon (IFN-I) response during viral infection [20]. Recently, a potent and selective small molecule inhibitor of PARP7, RBN-2397, was reported to enhance IFN-I signaling and cause lung cancer regression in xenograft models [21].  
CRISPR-Cas9 screens have identified PARP7 as a potential therapeutic target for several human cancers [22]. Compared with healthy tissue, PARP7 expression is reduced in a range of cancers, including breast cancer where higher PARP7 levels have been associated with a better outcome. PARP7 is expressed at higher levels in estrogen receptor (ER) and progesterone receptor (PR) positive breast tumors compared with ER and PR negative breast tumors [22]. Moreover, patients with advanced stages of breast cancer have lower expression levels of PARP7 [22].  
Estrogen receptor \(\alpha\) (ER\(\alpha\)) is the dominant regulator of estrogen action in breast tissue maintenance and mammary gland development [23], and the principal therapeutic target for breast cancer treatment [24]. ER\(\alpha\) contains several structurally conserved domains that are important for its functions. The A/B domains contain the activation function 1 (AF-1) region that facilitates ligand-independent activation. The DNA binding domain (DBD) is located in the C domain and is involved in binding to estrogen response elements (EREs) found in the regulatory regions of ER target genes. The D domain, known as the hinge region, acts as a flexible linker important for correct conformational changes, and contains a putative NLS. The E domain contains the ligand-dependent AF-2 region and the ligand-binding domain (LBD) [25; 26]. Recent studies have suggested that 17%-estradiol (E2) induces expression of PARP7, and that PARP7 promotes the proteolytic degradation of ER\(\alpha\)[19]; however, the underlying mechanisms are not well understood. In this study, we sought to investigate whether PARP7 regulates ER\(\alpha\) by mono-ADP-ribosylation. Our findings show that ER\(\alpha\) regulates PARP7 expression, and that PARP7 acts as a negative regulator of ER\(\alpha\) activity via mono-ADP-ribosylation in human breast cancer cells.