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Phosphatases and microRNAs: Investig...

Acharya, Sanket Shyamkant.

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Phosphatases and microRNAs: Investigations in the Context of DNA Damage.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Phosphatases and microRNAs: Investigations in the Context of DNA Damage./
Author:	Acharya, Sanket Shyamkant.
Description:	226 p.
Notes:	Source: Dissertation Abstracts International, Volume: 77-09(E), Section: B.
Contained By:	Dissertation Abstracts International77-09B(E).
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10102850
ISBN:	9781339664781

Phosphatases and microRNAs: Investigations in the Context of DNA Damage.
Acharya, Sanket Shyamkant.

Phosphatases and microRNAs: Investigations in the Context of DNA Damage. - 226 p.

Source: Dissertation Abstracts International, Volume: 77-09(E), Section: B.

Thesis (Ph.D.)--Harvard University, 2016.

Integrity of the cellular genome is constantly threatened by various sources of DNA damage that cause a variety of lesions including double strand breaks. Cells respond to such insults by upregulating the DNA damage response, a carefully orchestrated set of molecular events that leads to transcriptional changes, cell cycle arrest and/or apoptosis. In this dissertation we provide evidence supporting a role for phosphatases and microRNAs (miRNAs) in the cellular response to DNA damage.

ISBN: 9781339664781Subjects--Topical Terms:

517296
Molecular biology.

Phosphatases and microRNAs: Investigations in the Context of DNA Damage.
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020 $a 9781339664781
035 $a (MiAaPQ)AAI10102850
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100 1 $a Acharya, Sanket Shyamkant. $3 3192717
245 1 0 $a Phosphatases and microRNAs: Investigations in the Context of DNA Damage.
300 $a 226 p.
500 $a Source: Dissertation Abstracts International, Volume: 77-09(E), Section: B.
502 $a Thesis (Ph.D.)--Harvard University, 2016.
520 $a Integrity of the cellular genome is constantly threatened by various sources of DNA damage that cause a variety of lesions including double strand breaks. Cells respond to such insults by upregulating the DNA damage response, a carefully orchestrated set of molecular events that leads to transcriptional changes, cell cycle arrest and/or apoptosis. In this dissertation we provide evidence supporting a role for phosphatases and microRNAs (miRNAs) in the cellular response to DNA damage.
520 $a 53BP1 (tumor suppressor p53 binding protein 1) is a critical mediator of DNA repair signaling and its activity is regulated by several post-translational modifications. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in the ubiquitination-dependent recruitment motif. These residues are dephosphorylated in late mitosis/early G1 by the PP4C/R3beta phosphatase complex, which is required for 53BP1 accumulation at DNA breaks. We discovered that R3beta preferentially interacts with 53BP1 in stalled mitosis and determined that this interaction is dependent on the phosphorylation of R3beta residue S840 by the cyclin-dependent kinase family member CDK5. We also found that 53BP1 is deliberately excluded from chromatin during mitosis to prevent genomic instability. Ectopic reactivation of 53BP1 in mitosis causes increased micronuclei and lagging chromosome formation, which can be partially reversed by inhibiting the non-homologous end-joining pathway.
520 $a In a more clinical scenario, accidental radiation exposure can cause DNA damage that manifests itself in complex malignancies including bone marrow failure and cancer. In order to accurately predict radiation exposure for better management of radiation accidents, we identified serum microRNA (miRNA) signatures capable of indicating the long-term impact of total body irradiation in animals. Using different doses of radiation we systematically studied the impact of TBI on the hematopoietic system and then identified three miRNA signatures that effectively distinguished between animals exposed to control, sublethal, and lethal radiation. Furthermore, we used radioprotective and radiomitigating agents to show that serum miRNAs can predict not only the dose of radiation but also its impact on animal health. Finally, to investigate the relevance of these miRNAs in humans, we validated our findings in a humanized mouse model.
590 $a School code: 0084.
650 4 $a Molecular biology. $3 517296
650 4 $a Cellular biology. $3 3172791
690 $a 0307
690 $a 0379
710 2 $a Harvard University. $b Medical Sciences. $3 3181716
773 0 $t Dissertation Abstracts International $g 77-09B(E).
790 $a 0084
791 $a Ph.D.
792 $a 2016
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10102850