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Characterization of double-strand br...

Unal, Elcin.

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Characterization of double-strand break-induced cohesin domain assembly and function.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Characterization of double-strand break-induced cohesin domain assembly and function./
Author:	Unal, Elcin.
Description:	253 p.
Notes:	Adviser: Douglas E. Koshland.
Contained By:	Dissertation Abstracts International68-11B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3288547
ISBN:	9780549313946

Characterization of double-strand break-induced cohesin domain assembly and function.
Unal, Elcin.

Characterization of double-strand break-induced cohesin domain assembly and function. - 253 p.

Adviser: Douglas E. Koshland.

Thesis (Ph.D.)--The Johns Hopkins University, 2008.

DNA dependent processes including transcription, replication, repair and chromosome segregation are all influenced by chromosome structure. Chromosome structure, in turn is shaped by the protein complexes that contain members of the Structural Maintenance of Chromosome (SMC) family. One of these protein complexes called cohesin has been implicated in accurate chromosome segregation and post-replicative repair of double-strand breaks (DSBs). Cohesin mediates sister chromatid cohesion by tethering sister chromatids from the time of their replication until their segregation in anaphase. It was thought that cohesin-mediated tethering established exclusively during S phase by Ctf7 is necessary and sufficient to ensure post-replicative DSB repair. In this study, we show that DSBs induce de novo recruitment of cohesins to the broken chromosomes and trigger activation of sister chromatid cohesion in post-replicative cells. Using budding yeast, we demonstrate that a single DSB induces the formation of a &sim;100 kb cohesin domain around the lesion. Our analyses suggest that the primary DNA damage checkpoint kinases, Mec1 or Tel1, phosphorylate histone H2AX to generate a large domain, which is permissive for cohesin binding. Cohesin binding to the phospho-H2AX domain is enabled by Mre11/Rad50/Xrs2 repair complex, as well as the components of the cohesin loading machinery. We further show DSBs induce genome-wide activation of sister chromatid cohesion in post-replicative cells by a Ctf7-dependent but replication-independent mechanism, challenging the prevalent view on cohesion establishment. Our studies reveal that Ctf7 has two functions; a cohesive activity and a conserved acetyltransferase activity, which triggers the generation of cohesion in response to the DSB and the DNA damage checkpoint. Finally, we provide evidence that the DSB induced cohesin is necessary for the efficiency as well as the specificity of post-replicative repair and that DSB-induced cohesion supports the fidelity of broken and to an extent unbroken chromosomes in response to DSBs. Altogether, our results implicate the direct involvement of cohesin complex in the maintenance of genomic integrity upon DNA damage and suggest that perturbations of DSB-specific cohesin pathway might play a role in tumorigenesis.

ISBN: 9780549313946Subjects--Topical Terms:

1017686
Biology, Cell.

Characterization of double-strand break-induced cohesin domain assembly and function.
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100 1 $a Unal, Elcin. $3 1263084
245 1 0 $a Characterization of double-strand break-induced cohesin domain assembly and function.
300 $a 253 p.
500 $a Adviser: Douglas E. Koshland.
500 $a Source: Dissertation Abstracts International, Volume: 68-11, Section: B, page: 7131.
502 $a Thesis (Ph.D.)--The Johns Hopkins University, 2008.
520 $a DNA dependent processes including transcription, replication, repair and chromosome segregation are all influenced by chromosome structure. Chromosome structure, in turn is shaped by the protein complexes that contain members of the Structural Maintenance of Chromosome (SMC) family. One of these protein complexes called cohesin has been implicated in accurate chromosome segregation and post-replicative repair of double-strand breaks (DSBs). Cohesin mediates sister chromatid cohesion by tethering sister chromatids from the time of their replication until their segregation in anaphase. It was thought that cohesin-mediated tethering established exclusively during S phase by Ctf7 is necessary and sufficient to ensure post-replicative DSB repair. In this study, we show that DSBs induce de novo recruitment of cohesins to the broken chromosomes and trigger activation of sister chromatid cohesion in post-replicative cells. Using budding yeast, we demonstrate that a single DSB induces the formation of a &sim;100 kb cohesin domain around the lesion. Our analyses suggest that the primary DNA damage checkpoint kinases, Mec1 or Tel1, phosphorylate histone H2AX to generate a large domain, which is permissive for cohesin binding. Cohesin binding to the phospho-H2AX domain is enabled by Mre11/Rad50/Xrs2 repair complex, as well as the components of the cohesin loading machinery. We further show DSBs induce genome-wide activation of sister chromatid cohesion in post-replicative cells by a Ctf7-dependent but replication-independent mechanism, challenging the prevalent view on cohesion establishment. Our studies reveal that Ctf7 has two functions; a cohesive activity and a conserved acetyltransferase activity, which triggers the generation of cohesion in response to the DSB and the DNA damage checkpoint. Finally, we provide evidence that the DSB induced cohesin is necessary for the efficiency as well as the specificity of post-replicative repair and that DSB-induced cohesion supports the fidelity of broken and to an extent unbroken chromosomes in response to DSBs. Altogether, our results implicate the direct involvement of cohesin complex in the maintenance of genomic integrity upon DNA damage and suggest that perturbations of DSB-specific cohesin pathway might play a role in tumorigenesis.
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