USP17L2 Regulates Chemoresistance And DNA Damage Repair Through SIRT7

The malignant tumors are caused by the combination of environmental changes and related genetic factors,which lead to DNA damage and genomic instability in a sequential or synergistic way,and are one of the important reasons for the occurrence of malignant tumors.With the rapid development of medicine,the treatment of malignant tumors has been further developed from traditional surgery,radiotherapy and chemotherapy,and more treatment strategies have been expanded,such as molecular targeted therapy,cell therapy and immunotherapy.How to achieve high efficiency,low toxicity and low drug resistance in the process of malignant tumor treatment is an important goal of its treatment.Therefore,the chemoresistance of tumors has always been a research hotspot.Proteins are the effectors of life activities and are regulated in many aspects and levels.The modifications of proteins include:ubiquitination,acetylation,glycosylation,phosphorylation,alkylation and SUMO and the reversible processes of these modifications.Among which,ubiquitination is a process in which ubiquitin chains bind to target proteins,and is an important post-translational modification of proteins.Through ubiquitination,the stability of the target protein is reduced and the target protein is degraded.However,deubiquitination is the opposite process of ubiquitination.Current research has confirmed that there are a variety of deubiquitinating enzymes,which participate in the regulation of tumor occurrence,development and chemoresistance by selectively degrading or stabilizing oncogenes and tumor suppressor genes.For example,there are reported recently the deubiquitinase USP20 promotes tumor growth,migration,invasion and chemoresistance by positively regulating the stability ofβ-catenin.The deubiquitinase USP13deubiquitinates the Receptor-associated protein 80(RAP80)signaling axis-dependent DNA damage response mechanism,thereby regulating the molecular mechanism of ovarian cancer chemoresistance andthe UCHL3 deubiquitinates the signaling cascade of DNA damage protein RAD51 in homologous recombination repair to regulate the molecular mechanism of breast cancer chemo-resistance.These published articles illustrate the molecular mechanisms by which deubiquitinases regulate tumor chemoresistance.Sirtuin proteins are a group of NAD~+-dependent histone deacetylases.Humans have seven sirtuin homologs,Sirtuin1-Sirtuin7,with different subcellular localization and functions.The Sirtuin protein family participates in the regulation of cell senescence,glucose and lipid metabolism,stress response,inflammatory response,and tumor development by changing the activity and stability of proteins.As a member of the Sirtuins protein family,SIRT7 is located in the nucleolus and is a nicotinamide adenine dinucleic acid-dependent histone deacetylase that can specifically deacetylate the 18th lysine residue of histone H3.SIRT7 is involved in a variety of cellular activities in vivo,including:cell proliferation,cell metabolism,DNA damage repair and stress response,and is closely related to the occurrence,development and chemoresistance of tumors.It has been reported that the deubiquitinase USP7 mediates the polyubiquitin chain of SIRT7 to regulate the process of gluconeogenesis.However,the current research on the regulation of protein stability of SIRT7 by deubiquitinating enzymes is still unclear.In addition,whether the deubiquitinating enzyme regulates DNA damage repair through SIRT7 to mediate tumor resistance in cancer is still unclear.The main contents and main results in this paper are as follows:1.Mass spectrometry analysis and co-immunoprecipitation(co-IP)experiments revealed that USP17L2 is an interacting protein of SIRT72.USP17L2 stabilizes SIRT7 using protein stability experiment.3.USP17L2 deubiquitinates SIRT7 in vivo and in vitro4.USP17L2 positively regulates DNA damage repair via SIRT7 by homologous recombination and non-homologous end joining reporting systems.5.USP17L2 regulates chemoresistance of breast cancer cells through SIRT7 by cell survival assays.6.USP17L2 expression correlates with SIRT7 levels in clinical breast cancer samples by Immunohistochemical(IHC)staining experiments,and a high expression level of USP17L2 is associated with poor prognosis in breast cancer patients.