Abstract: The present disclosure provides methods and compositions for high frequency, targeted mammalian transgenesis using, for example, a two-step, two-stage process that enables integrating anywhere in the mammalian genome large pieces of nucleic acid in single generation.

Abstract: A genetically modified NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mouse is provided by the present invention wherein the genome of the mouse includes a mutated Rhbdf2 gene such that the mouse expresses a mutant iRhom2 protein, wherein the mutant iRhom2 protein differs from wild-type iRhom2 protein due to one or more mutations selected from p.I156T, p.D158N and p.P159L, and wherein the mouse is characterized by hairless phenotype and increased growth of an exogenous tumor compared to a mouse of the same genetic background which express wild-type iRhom2 protein.

Abstract: Methods for identifying a compound that modulates activity of an iRhom polypeptide according to aspects of the present invention are described herein which include contacting a cell expressing an iRhom polypeptide with a test compound; and determining the effect of the compound on activity of the iRhom polypeptide. Detection of a decrease in proteolytic activity of the iRhom polypeptide indicates that the compound is capable of one or more of: reducing tumor growth, reducing tumor progression, treatment of cancer and promoting hair growth in a subject, and detecting an increase in proteolytic activity of the iRhom polypeptide indicates that the compound is capable of accelerating wound healing in a subject.