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Three Subfamilies of KRAB Zinc Finger Proteins: A Structural, Functional and Evolutionary Analysis
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Krüppel-related zinc finger proteins constitute the largest single class of transcription factors within the human genome. Members of this protein family have the ability to either activate or repress transcription depending on the presence of specific activator or repressor domains within the protein. Approximately one third of the Krüppel-related zinc finger proteins contain an evolutionarily well-conserved repressor domain termed the KRAB domain. This domain acts as a potent repressor of transcription by interacting with the co-repressor protein, TIF1β. TIF1β then, in turn, recruits HP1 proteins, HDACs and probably other proteins involved in gene silencing. In order to identify novel KRAB-containing zinc finger proteins, one mouse monocytic cDNA library and two testis cDNA libraries were screened for novel members of this multigene family. Six novel KRAB-ZNF cDNAs, four mouse and two human, were isolated. The corresponding proteins were all shown to contain N-terminally located KRAB domains as well as varying numbers of C-terminally located zinc finger motifs. An extensive comparative sequence analysis of the KRAB domains of these proteins together with KRAB domains from a large number of previously identified KRAB-ZNF proteins resulted in a clear subdivision into three different subfamilies, A+B, A+b and A. Later, we also isolated a fourth KRAB box, which is present downstream of the KRAB A box in a few proteins of the KRAB A family. This module was named KRAB C. Potential functional differences between these different subfamilies were investigated. In line with previous observations, the KRAB A box was shown to repress transcription, an activity which was enhanced by the presence of the KRAB B box. However, addition of neither the KRAB b box nor the KRAB C box had any effect on repression. Moreover, all KRAB A motifs had the ability to bind TIF1β, and this binding was increased both by the presence of the KRAB B box and by the KRAB C box. The KRAB b box, however, did not seem to contribute to TIF1β-binding. One of the novel human cDNAs, HKr19, was found to be a member of the large ZNF91 family of KRAB zinc finger genes. Interestingly, the expression of HKr19 and a number of other closely related genes were restricted to lymphoid cells, indicating that these genes may be involved in regulating lineage commitment. The effect of HKr19 on cell viability was investigated by transfection into human embryonic kidney cells (HEK 293). The results indicated that HKr19, or its zinc finger domain in isolation, were toxic to these cells when expressed at high levels. The MZF6D protein, on the other hand, showed a testis-specific expression. In situ hybridization analysis located this expression to meiotic germ cells, suggesting a role for this protein in spermatogenesis. Further, the evolutionary perspectives of this large gene family were addressed, and its enormous expansion throughout evolution probably includes numerous duplication events. The results from two extensive sequence analyses give clues to how the repetitive nature of the ZNF motif has given rise to both internal duplications of single motifs as well as duplications of entire genes resulting in gene clusters.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 52
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 863
Keywords [en]
Biology, Krüppel zinc finger, KRAB, TIF1β, transcriptional repression
Keywords [sv]
Biologi
National Category
Biological Sciences
Research subject
Molecular Immunology
Identifiers
URN: urn:nbn:se:uu:diva-3512ISBN: 91-554-5683-9 (print)OAI: oai:DiVA.org:uu-3512DiVA, id: diva2:163072
Public defence
2003-10-04, C11:305, Biomedicinskt centrum, Uppsala, 09:15
Opponent
Supervisors
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved
List of papers
1. Comarative Analysis of KRAB Zinc Finger Proteins in Rodents and Man: Evidence for Several Evolutionarily Distinct Subfamilies of KRAB Zinc Finger Genes
Open this publication in new window or tab >>Comarative Analysis of KRAB Zinc Finger Proteins in Rodents and Man: Evidence for Several Evolutionarily Distinct Subfamilies of KRAB Zinc Finger Genes
1999 In: DNA Cell Biol., Vol. 18, no 5, p. 381-396Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90632 (URN)
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved
2. Molecular Cloning and Functional Analysis of Two Novel Human KRAB Zinc Finger Proteins, HKr18 and HKr19
Open this publication in new window or tab >>Molecular Cloning and Functional Analysis of Two Novel Human KRAB Zinc Finger Proteins, HKr18 and HKr19
2001 In: DNA Cell Biol., Vol. 20, no 5, p. 275-286Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90633 (URN)
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved
3. Conserved Interaction Between Distinct Krüppel-associated box Domains and the Transcriptional Intermediary factor 1β
Open this publication in new window or tab >>Conserved Interaction Between Distinct Krüppel-associated box Domains and the Transcriptional Intermediary factor 1β
Show others...
2001 In: Procl. Natl. Acad. Sci. USA, Vol. 98, no 4, p. 1422-1426Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90634 (URN)
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved
4. KRAB Zinc Finger Proteins: An Analysis of the Molecular Mechanisms Governing Their Increase in Numbers and Complexity During Evolution
Open this publication in new window or tab >>KRAB Zinc Finger Proteins: An Analysis of the Molecular Mechanisms Governing Their Increase in Numbers and Complexity During Evolution
2002 In: Mol. Biol. Evol., ISSN 0737-4038, Vol. 19, no 12, p. 2118-2130Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90635 (URN)
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved
5. MZF6D, a Novel KRAB Zinc Finger Gene Expressed Exclusively in Meiotic Male Germ Cells
Open this publication in new window or tab >>MZF6D, a Novel KRAB Zinc Finger Gene Expressed Exclusively in Meiotic Male Germ Cells
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-90636 (URN)
Available from: 2003-09-01 Created: 2003-09-01Bibliographically approved

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