Regulation of DNA Duplication by the MTOR Signaling Pathway

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2021 Mar 11

PMID 33691584

Citations 8

Authors

Zhengfu He

Peter J Houghton

Terence M Williams

Changxian Shen

Affiliations

Soon will be listed here.

Abstract

Accurate and complete DNA replication and separation are essential for genetic information inheritance and organism maintenance. Errors in DNA duplication are the main source of genetic instability. Understanding DNA duplication regulation is the key to elucidate the mechanisms and find treatment strategies for human genetic disorders, especially cancer. The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and proliferation by integrating and processing extracellular and intracellular signals to monitor the well-being of cell physiology. mTOR signaling dysregulation is associated with many human diseases including cancer and diabetes. Emerging evidence has demonstrated that mTOR signaling plays a key role in DNA duplication. We herein review the current knowledge of mTOR signaling in the regulation of DNA replication origin licensing, replication fork progression, and stabilization.

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References

Rundle S, Bradbury A, Drew Y, Curtin N . Targeting the ATR-CHK1 Axis in Cancer Therapy. Cancers (Basel). 2017; 9(5). PMC: 5447951. DOI: 10.3390/cancers9050041. View

Grasso D, Renna F, Vaccaro M . Initial Steps in Mammalian Autophagosome Biogenesis. Front Cell Dev Biol. 2018; 6:146. PMC: 6206277. DOI: 10.3389/fcell.2018.00146. View

Wullschleger S, Loewith R, Hall M . TOR signaling in growth and metabolism. Cell. 2006; 124(3):471-84. DOI: 10.1016/j.cell.2006.01.016. View

Chaudhury I, Sareen A, Raghunandan M, Sobeck A . FANCD2 regulates BLM complex functions independently of FANCI to promote replication fork recovery. Nucleic Acids Res. 2013; 41(13):6444-59. PMC: 3711430. DOI: 10.1093/nar/gkt348. View

Nguyen J, Ray C, Fox A, Mendonca D, Kim J, Krebsbach P . Mammalian EAK-7 activates alternative mTOR signaling to regulate cell proliferation and migration. Sci Adv. 2018; 4(5):eaao5838. PMC: 5942914. DOI: 10.1126/sciadv.aao5838. View

Fingar D, Richardson C, Tee A, Cheatham L, Tsou C, Blenis J . mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2003; 24(1):200-16. PMC: 303352. DOI: 10.1128/MCB.24.1.200-216.2004. View

Huang M, Zhou Z, Elledge S . The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor. Cell. 1998; 94(5):595-605. DOI: 10.1016/s0092-8674(00)81601-3. View

Guo F, Li J, Du W, Zhang S, OConnor M, Thomas G . mTOR regulates DNA damage response through NF-κB-mediated FANCD2 pathway in hematopoietic cells. Leukemia. 2013; 27(10):2040-2046. PMC: 4225699. DOI: 10.1038/leu.2013.93. View

Harwood F, Geltink R, OHara B, Cardone M, Janke L, Finkelstein D . ETV7 is an essential component of a rapamycin-insensitive mTOR complex in cancer. Sci Adv. 2018; 4(9):eaar3938. PMC: 6156121. DOI: 10.1126/sciadv.aar3938. View

10.

Oka K, Ohya-Shimada W, Mizuno S, Nakamura T . Up-regulation of cyclin-E(1) via proline-mTOR pathway is responsible for HGF-mediated G(1)/S progression in the primary culture of rat hepatocytes. Biochem Biophys Res Commun. 2013; 435(1):120-5. DOI: 10.1016/j.bbrc.2013.04.052. View

11.

Bristow R, Hill R . Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008; 8(3):180-92. DOI: 10.1038/nrc2344. View

12.

Zhou X, Liu W, Hu X, Dorrance A, Garzon R, Houghton P . Regulation of CHK1 by mTOR contributes to the evasion of DNA damage barrier of cancer cells. Sci Rep. 2017; 7(1):1535. PMC: 5431544. DOI: 10.1038/s41598-017-01729-w. View

13.

Knipscheer P, Raschle M, Smogorzewska A, Enoiu M, Ho T, Scharer O . The Fanconi anemia pathway promotes replication-dependent DNA interstrand cross-link repair. Science. 2009; 326(5960):1698-701. PMC: 2909596. DOI: 10.1126/science.1182372. View

14.

Cimprich K, Cortez D . ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8):616-27. PMC: 2663384. DOI: 10.1038/nrm2450. View

15.

Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X . TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell. 2006; 126(5):955-68. DOI: 10.1016/j.cell.2006.06.055. View

16.

Joo W, Xu G, Persky N, Smogorzewska A, Rudge D, Buzovetsky O . Structure of the FANCI-FANCD2 complex: insights into the Fanconi anemia DNA repair pathway. Science. 2011; 333(6040):312-6. PMC: 3310437. DOI: 10.1126/science.1205805. View

17.

Kim E, Goraksha-Hicks P, Li L, Neufeld T, Guan K . Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008; 10(8):935-45. PMC: 2711503. DOI: 10.1038/ncb1753. View

18.

Tamborero D, Gonzalez-Perez A, Perez-Llamas C, Deu-Pons J, Kandoth C, Reimand J . Comprehensive identification of mutational cancer driver genes across 12 tumor types. Sci Rep. 2013; 3:2650. PMC: 3788361. DOI: 10.1038/srep02650. View

19.

Lee D, Kuo H, Chen C, Hsu J, Chou C, Wei Y . IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell. 2007; 130(3):440-55. DOI: 10.1016/j.cell.2007.05.058. View

20.

Polak P, Hall M . mTOR and the control of whole body metabolism. Curr Opin Cell Biol. 2009; 21(2):209-18. DOI: 10.1016/j.ceb.2009.01.024. View