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Coordinate transcriptional control b...

Tan, Wei.

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Coordinate transcriptional control by ZBRK1 and BRCA1.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Coordinate transcriptional control by ZBRK1 and BRCA1./
Author:	Tan, Wei.
Description:	176 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-01, Section: B, page: 0120.
Contained By:	Dissertation Abstracts International66-01B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3161336
ISBN:	0496947303

Coordinate transcriptional control by ZBRK1 and BRCA1.
Tan, Wei.

Coordinate transcriptional control by ZBRK1 and BRCA1. - 176 p.

Source: Dissertation Abstracts International, Volume: 66-01, Section: B, page: 0120.

Thesis (Ph.D.)--The University of Texas Health Science Center at San Antonio, 2005.

The breast- and ovarian-specific tumor suppressor BRCA1 functions in the maintenance of global genome stability. The underlying basis for the caretaker activity of BRCA1 has been ascribed in part to its role in transcription control of DNA damage-response genes. In this regard, BRCA1 has been implicated in both gene-specific transcriptional activation and repression by virtue of its direct interaction and functional synergy with sequence-specific DNA -inding transcription factors. Among these, ZBRK1 is a BRCA1-dependent repressor of the DNA damage response gene GADD45alpha and a member of the KRAB-ZFP family of transcriptional repressors.

ISBN: 0496947303Subjects--Topical Terms:

1017719
Biology, Molecular.

Coordinate transcriptional control by ZBRK1 and BRCA1.
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100 1 $a Tan, Wei. $3 1029215
245 1 0 $a Coordinate transcriptional control by ZBRK1 and BRCA1.
300 $a 176 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-01, Section: B, page: 0120.
500 $a Adviser: Thomas G. Boyer.
502 $a Thesis (Ph.D.)--The University of Texas Health Science Center at San Antonio, 2005.
520 $a The breast- and ovarian-specific tumor suppressor BRCA1 functions in the maintenance of global genome stability. The underlying basis for the caretaker activity of BRCA1 has been ascribed in part to its role in transcription control of DNA damage-response genes. In this regard, BRCA1 has been implicated in both gene-specific transcriptional activation and repression by virtue of its direct interaction and functional synergy with sequence-specific DNA -inding transcription factors. Among these, ZBRK1 is a BRCA1-dependent repressor of the DNA damage response gene GADD45alpha and a member of the KRAB-ZFP family of transcriptional repressors.
520 $a With respect to DNA-binding, electrophoretic mobility shift assays using recombinant ZBRK1 derivatives delimited the core ZBRK1 DNA-binding domain to zinc fingers 1--4. Zinc fingers 5--8 along with C-terminus are modulatory for ZBRK1 DNA-binding. With respect to BRCA1-binding, yeast two hybrid protein-protein interaction assays revealed that important BRCA1-binding determinants on ZBRK1 include zinc fingers 7 and 8 as well as the C-terminus, surfaces that either positively (zinc finger 7) or negatively (zinc finger 8 and the C-terminus) influence the DNA-binding activity of ZBRK1.
520 $a Transit transfection experiments confirmed that BRCA1 could mediate repression by DNA-bound ZBRK1 and further identified a novel BRCA1-dependent C-terminal transcriptional repression domain (CTRD) within ZBRK1 that extends from zinc finger 5 to the C-terminus. Functionally, the CTRD repressed transcription in a BRCA1-dependent, histone deacetylase (HDAC)-dependent, and promoter-specific manner, and was thus distinguishable from an N-terminal KRAB repression domain in ZBRK1, which exhibited no BRCA1-dependency and broad promoter-specificity.
520 $a Immobilized protein affinity chromatography and co-immunoprecipitation analyses using wild-type and mutant ZBRK1 derivatives confirmed that ZBRK1 homo-oligomerized in vitro and in vivo, and identified the CTRD C-terminal 9 amino acids to be critical for oligomerization. Biochemical analyses revealed that ZBRK1 homo-oligomers existed as tetramers in solution. Functionally, ZBRK1 oligomerization supports ZBRK1-directed transcriptional repression through ZBRK1 response elements (ZREs); structural requirements for oligomerization-dependent repression include the CTRD and the KRAB repression domains within ZBRK1.
520 $a A chimeric transcriptional activator comprised of ZBRK1 KRAB domain-deletion derivative fused to the BRCA1-independent transactivation domain from the Herpes Simplex Virus VP16 transactivator activated transcription from a reporter template driven by ZREs in a BRCA1-dependent manner, indicating that BRCA1 is important for ZBRK1/ZRE interaction in vivo.
520 $a Collectively, this the studies described in this dissertation shed new light on the functional organization of ZBRK1 as a model KRAB-zinc finger protein and further define the role of BRCA1 in sequence-specific transcription control.
590 $a School code: 0853.
650 4 $a Biology, Molecular. $3 1017719
690 $a 0307
710 2 0 $a The University of Texas Health Science Center at San Antonio. $3 1030926
773 0 $t Dissertation Abstracts International $g 66-01B.
790 1 0 $a Boyer, Thomas G., $e advisor
790 $a 0853
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3161336