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Overcoming obstacles to nonhomologou...

The University of North Carolina at Chapel Hill., Biochemistry and Biophysics.

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Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks./
作者:	Roberts, Steven Andrew.
面頁冊數:	112 p.
附註:	Adviser: Dale Ramsden.
Contained By:	Dissertation Abstracts International69-11B.
標題:	Biophysics, General. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3331019
ISBN:	9780549881186

Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks.
Roberts, Steven Andrew.

Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks. - 112 p.

Adviser: Dale Ramsden.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2008.

Protein occlusions and oxidative nucleotide damages that flank chromosome double strand breaks are serious obstacles to nonhomologous end joining (NHEJ) since they each directly impact a specific step of this repair pathway. Because NHEJ requires the Ku heterodimer (a ring protein requiring 360° of access for binding) to recognize DNA ends, this pathway would seem particularly sensitive to DNA end-occlusions. End-associated nucleotide damages would also seemly present a significant obstacle to NHEJ as they specifically inhibit XRCC4-LigaseIV, and their proximity to DNA ends precludes their removal by traditional base excision repair enzymes.

ISBN: 9780549881186Subjects--Topical Terms:

1019105
Biophysics, General.

Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks.
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245 1 0 $a Overcoming obstacles to nonhomologous end joining repair of chromosome double strand breaks.
300 $a 112 p.
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500 $a Source: Dissertation Abstracts International, Volume: 69-11, Section: B, page: 6778.
502 $a Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2008.
520 $a Protein occlusions and oxidative nucleotide damages that flank chromosome double strand breaks are serious obstacles to nonhomologous end joining (NHEJ) since they each directly impact a specific step of this repair pathway. Because NHEJ requires the Ku heterodimer (a ring protein requiring 360° of access for binding) to recognize DNA ends, this pathway would seem particularly sensitive to DNA end-occlusions. End-associated nucleotide damages would also seemly present a significant obstacle to NHEJ as they specifically inhibit XRCC4-LigaseIV, and their proximity to DNA ends precludes their removal by traditional base excision repair enzymes.
520 $a Surprisingly, NHEJ is able to overcome these obstacles. I have shown that despite the potential steric conflicts, Ku readily binds protein-occluded DNA ends. Moreover, this very protein, predicted to be inhibited by end-associated protein obstructions, may specifically limit NHEJ's need for ATP-dependent chromatin remodeling as Ku readily evicts weakly bound DNA-associated proteins and peels DNA from strongly positioned nucleosomes.
520 $a In the case of end-associated nucleotide damages, NHEJ employs a large repertoire of processing factors, some displaying unique activity, to specifically remove, repair, or bypass these complex lesions. My work identifies a new part of this repertoire: Ku is novel AP lyase tailored to remove end-associated abasic sites and thereby facilitate joining of these complex breaks. Ku efficiently cleaves the phosphodiester backbone 3' of end-associated abasic sites, precisely removing damage in a context unfavorable to other known lyases.
520 $a Finally, my work suggests NHEJ ensures difficult breaks containing incompatible ends are repaired. This involves complementing the above processing based ligation with an additional, low fidelity ligation mechanism. XLF/Cernunnos, the key factor establishing this subpathway, functions to clamp XRCC4-LigaseIV to DNA ends and thereby stimulates LigaseIV's ability to ligate mismatched overhangs. Consequently, this activity allows NHEJ to join difficult DNA ends, potentially incorporating damaged nucleotides or mismatches into an intact chromosome, where they can be repaired without further risk of DNA translocation. Taken together, these unique activities highlight NHEJ's flexibility and sophistication in overcoming obstacles to preserve genome integrity.
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790 1 0 $a Griffith, Jack $e committee member
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790 1 0 $a Sekelsky, Jeff $e committee member
790 1 0 $a Zhang, Yi $e committee member
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