title: Spotting the enemy within: Targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family.
abstract: Tandem C2H2-type zinc finger proteins (ZFPs) constitute the largest transcription factor family in animals. Tandem-ZFPs bind DNA in a sequence-specific manner through arrays of multiple zinc finger domains that allow high flexibility and specificity in target recognition. In tetrapods, a large proportion of tandem-ZFPs contain Krüppel-associated-box (KRAB) repression domains, which are able to induce epigenetic silencing through the KAP1 corepressor. The KRAB-ZFP family continuously amplified in tetrapods through segmental gene duplications, often accompanied by deletions, duplications, and mutations of the zinc finger domains. As a result, tetrapod genomes contain unique sets of KRAB-ZFP genes, consisting of ancient and recently evolved family members. Although several hundred human and mouse KRAB-ZFPs have been identified or predicted, the biological functions of most KRAB-ZFP family members have gone unexplored. Furthermore, the evolutionary forces driving the extraordinary KRAB-ZFP expansion and diversification have remained mysterious for decades. In this review, we highlight recent studies that associate KRAB-ZFPs with the repression of parasitic DNA elements in the mammalian germ line and discuss the hypothesis that the KRAB-ZFP family primarily evolved as an adaptive genomic surveillance system against foreign DNA. Finally, we comment on the computational, genetic, and biochemical challenges of studying KRAB-ZFPs and attempt to predict how these challenges may be soon overcome.
authors.affiliation: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Gernot
authors.initials: G
authors.lastname: Wolf
authors.affiliation: The Gladstone Institute of Virology and Immunology, University of California, San Francisco, CA 94158 USA ; Present address: Pacific Biosciences, 1380 Willow Road, Menlo Park, CA 94025 USA.
authors.forename: David
authors.initials: D
authors.lastname: Greenberg
authors.affiliation: The Eunice Kennedy Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Todd S
authors.initials: TS
authors.lastname: Macfarlan
keywords: Adaptive evolution; Endogenous retroviruses; Epigenetic silencing; KRAB zinc finger proteins; Transcription factors; Transposable elements