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Regulation of MCM Helicase Loading D...

Matson, Jacob Peter.

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Regulation of MCM Helicase Loading During Early Differentiation and Cell Cycle Re-entry.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Regulation of MCM Helicase Loading During Early Differentiation and Cell Cycle Re-entry./
作者:	Matson, Jacob Peter.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	169 p.
附註:	Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Contained By:	Dissertations Abstracts International80-12B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13809303
ISBN:	9781392200872

Regulation of MCM Helicase Loading During Early Differentiation and Cell Cycle Re-entry.
Matson, Jacob Peter.

Regulation of MCM Helicase Loading During Early Differentiation and Cell Cycle Re-entry. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 169 p.

Source: Dissertations Abstracts International, Volume: 80-12, Section: B.

Thesis (Ph.D.)--The University of North Carolina at Chapel Hill, 2019.

This item must not be sold to any third party vendors.

Cells initiate DNA replication at thousands of DNA replication origins every cell cycle. Minichromosome maintenance complexes (MCM) unwind DNA to initiate replication in S phase. MCM loading onto DNA, called "origin licensing", occurs in G1 phase. Multiple mechanisms restrict origin licensing to G1 phase to prevent aberrant MCM loading and genotoxic re-replication in S phase. For this reason, cells load 5-10 fold excess MCM in G1 as dormant origins to protect against replication stress in S phase. The origin licensing checkpoint ensures sufficient MCM loading before S phase entry. MCM loading occurs in G1, yet cells have a variety of G1 lengths. Stem cells have short G1s while differentiated cells have long G1 phases. Additionally, cells may exit the cell cycle to quiescence, a state without division. Cells re-entering the cell cycle from quiescence have longer G1s than actively proliferating cells. How cells accomplish the same MCM loading under these different G1 lengths is poorly understood. We used quantitative single cell flow cytometry and live cell imaging to measure MCM loading across varying G1 lengths.We found that stem cells with short G1s load MCM significantly faster than differentiated cells with long G1s. MCM loading rate decreases and G1 length increases during stem cell differentiation to all germ layers. The rapid licensing is due to increased Cdt1 protein in stem cells. Rapid origin licensing is intrinsic to pluripotency, as slowing MCM loading in stem cells promotes their differentiation. Cells re-entering into long G1 phases from quiescence are underlicensed with less loaded MCM at S phase entry than proliferating cells. The underlicensing causes replication stress sensitivity in S phase, and repeated rounds of quiescence and re-entry increase the replication stress sensitivity. A defective origin licensing checkpoint combined with a slow MCM loading rate causes the underlicensing during cell cycle re-entry, and extending the first G1 phase rescues the underlicensing. Thus, cell cycle re-entry is a higher risk cell cycle than active proliferation. Proper regulation of the rate and amount of MCM loading is critical across different G1 types to control differentiation, proliferation and genome stability.

ISBN: 9781392200872Subjects--Topical Terms:

518028
Biochemistry.

Regulation of MCM Helicase Loading During Early Differentiation and Cell Cycle Re-entry.
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520 $a Cells initiate DNA replication at thousands of DNA replication origins every cell cycle. Minichromosome maintenance complexes (MCM) unwind DNA to initiate replication in S phase. MCM loading onto DNA, called "origin licensing", occurs in G1 phase. Multiple mechanisms restrict origin licensing to G1 phase to prevent aberrant MCM loading and genotoxic re-replication in S phase. For this reason, cells load 5-10 fold excess MCM in G1 as dormant origins to protect against replication stress in S phase. The origin licensing checkpoint ensures sufficient MCM loading before S phase entry. MCM loading occurs in G1, yet cells have a variety of G1 lengths. Stem cells have short G1s while differentiated cells have long G1 phases. Additionally, cells may exit the cell cycle to quiescence, a state without division. Cells re-entering the cell cycle from quiescence have longer G1s than actively proliferating cells. How cells accomplish the same MCM loading under these different G1 lengths is poorly understood. We used quantitative single cell flow cytometry and live cell imaging to measure MCM loading across varying G1 lengths.We found that stem cells with short G1s load MCM significantly faster than differentiated cells with long G1s. MCM loading rate decreases and G1 length increases during stem cell differentiation to all germ layers. The rapid licensing is due to increased Cdt1 protein in stem cells. Rapid origin licensing is intrinsic to pluripotency, as slowing MCM loading in stem cells promotes their differentiation. Cells re-entering into long G1 phases from quiescence are underlicensed with less loaded MCM at S phase entry than proliferating cells. The underlicensing causes replication stress sensitivity in S phase, and repeated rounds of quiescence and re-entry increase the replication stress sensitivity. A defective origin licensing checkpoint combined with a slow MCM loading rate causes the underlicensing during cell cycle re-entry, and extending the first G1 phase rescues the underlicensing. Thus, cell cycle re-entry is a higher risk cell cycle than active proliferation. Proper regulation of the rate and amount of MCM loading is critical across different G1 types to control differentiation, proliferation and genome stability.
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