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UVSSA Regulates Transcription-Coupled Genome Maintenance.

紀錄類型:	書目-語言資料,手稿 : Monograph/item
正題名/作者:	UVSSA Regulates Transcription-Coupled Genome Maintenance./
作者:	Liebau, Rowyn Church.
面頁冊數:	1 online resource (119 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
標題:	Molecular biology. -
電子資源:	click for full text (PQDT)
ISBN:	9798381097290

UVSSA Regulates Transcription-Coupled Genome Maintenance.
Liebau, Rowyn Church.

UVSSA Regulates Transcription-Coupled Genome Maintenance. - 1 online resource (119 pages)

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--Columbia University, 2024.

Includes bibliographical references

DNA damage is a constant threat to our genomes which drives genome instability and contributes to cancer progression. DNA damage interferes with important DNA transactions such as transcription and replication. DNA lesions are removed by repair pathways that ensure genome stability during transcription and replication. Here, we identify and characterize distinct roles for the ultra violet stimulated scaffold protein A (UVSSA) in the maintenance of genome stability during transcription in human cells. First, we unravel a novel function for UVSSA in transcription-coupled repair of DNA interstrand crosslinks (ICLs), genotoxic adducts that covalently bind opposing strands of the DNA and block transcription and replication. UVSSA knockout cells are sensitive to ICL inducing drugs, and UVSSA is specifically required for transcription-coupled repair of ICLs in a fluorescence-based reporter assay. Based on analysis of the UVSSA protein interactome in crosslinker treated cells we propose a model for transcription-coupled ICL repair (TC-ICR) that is initiated by stalling of transcribing RNA polymerase II (Pol II) at an ICL. Stalled Pol II is first bound by CSA and CSB, followed by UVSSA which recruits TFIIH to initiate downstream lesion removal steps. Second, we establish that UVSSA counteracts MYC dependent transcription stress to promote genome stability in cells aberrantly expressing the cMYC oncogene. UVSSA knockdown sensitizes cells to MYC expression, resulting in synthetic sickness and increased doubling time. UVSSA knockdown impacts Pol II dynamics in MYC activated cells. We conclude that UVSSA is required for regulation of Pol II during MYC induced transcription to prevent transcription stress. Together, these studies expand our understanding of UVSSA's role in genome stability during transcription and elucidates the poorly understood transcription-coupled ICL repair pathway.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381097290Subjects--Topical Terms:

583443
Molecular biology.
Subjects--Index Terms:

Genome integrityIndex Terms--Genre/Form:

554714
Electronic books.

UVSSA Regulates Transcription-Coupled Genome Maintenance.
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520 $a DNA damage is a constant threat to our genomes which drives genome instability and contributes to cancer progression. DNA damage interferes with important DNA transactions such as transcription and replication. DNA lesions are removed by repair pathways that ensure genome stability during transcription and replication. Here, we identify and characterize distinct roles for the ultra violet stimulated scaffold protein A (UVSSA) in the maintenance of genome stability during transcription in human cells. First, we unravel a novel function for UVSSA in transcription-coupled repair of DNA interstrand crosslinks (ICLs), genotoxic adducts that covalently bind opposing strands of the DNA and block transcription and replication. UVSSA knockout cells are sensitive to ICL inducing drugs, and UVSSA is specifically required for transcription-coupled repair of ICLs in a fluorescence-based reporter assay. Based on analysis of the UVSSA protein interactome in crosslinker treated cells we propose a model for transcription-coupled ICL repair (TC-ICR) that is initiated by stalling of transcribing RNA polymerase II (Pol II) at an ICL. Stalled Pol II is first bound by CSA and CSB, followed by UVSSA which recruits TFIIH to initiate downstream lesion removal steps. Second, we establish that UVSSA counteracts MYC dependent transcription stress to promote genome stability in cells aberrantly expressing the cMYC oncogene. UVSSA knockdown sensitizes cells to MYC expression, resulting in synthetic sickness and increased doubling time. UVSSA knockdown impacts Pol II dynamics in MYC activated cells. We conclude that UVSSA is required for regulation of Pol II during MYC induced transcription to prevent transcription stress. Together, these studies expand our understanding of UVSSA's role in genome stability during transcription and elucidates the poorly understood transcription-coupled ICL repair pathway.
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