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Chromatin dynamics in senescence: a ...

Duarte, Luis Felipe.

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Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form./
Author:	Duarte, Luis Felipe.
Description:	163 p.
Notes:	Source: Dissertation Abstracts International, Volume: 76-08(E), Section: B.
Contained By:	Dissertation Abstracts International76-08B(E).
Subject:	Oncology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3687006
ISBN:	9781321642414

Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form.
Duarte, Luis Felipe.

Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form. - 163 p.

Source: Dissertation Abstracts International, Volume: 76-08(E), Section: B.

Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2015.

Oncogene-induced senescence (OIS) is characterized by irreversible loss of proliferative capacity. Senescence induction depends on the p53 and Rb signaling pathways, which cooperate to ensure cell cycle arrest. OIS functions as a tumor suppressor mechanism, and several studies have demonstrated induction of senescence markers in pre-malignant lesions. For example, melanocytes within human nevi often harbor an activating mutation in BRAF (BRAFV600E) and can remain senescent for decades. In addition to profound morphological changes, significant alterations in chromatin structure occur during senescence including formation of senescence-associated heterochromatin foci (SAHF). SAHFs are enriched in heterochromatic markers including H3K9me3 and the histone variant macroH2A. Further, there is a re-distribution of histone post-translational modifications (PTMs) in senescent cells, with global loss of euchromatic markers concomitant with enrichment of heterochromatin-inducing PTMs. While it is now well established that cellular senescence generates a repressive chromatin environment, the role of histone variants and histone modifications such as proteolytic cleavage remains unclear. Using models of oncogene-induced and replicative senescence, we identified novel histone H3 tail cleavage events mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and that the histone variant H3.3 is the preferred form. Cleavage of H3 tail has been described in other models including Tetrahymena micronuclei and differentiated mouse ES cells. However, no direct biological role for the cleaved form of histone H3 has been described. Here, we show that ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first twenty-one amino acids, is sufficient to induce senescence. Further, H3.3cs1 chromatin incorporation is mediated by the histone chaperone ASF1a, which has previously been shown to play an important role during OIS. Genome-wide transcriptional profiling indicates that H3 tail cleavage facilitates transcriptional silencing of cell cycle regulators including Rb/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, my study provides the first example of proteolytic processing of a histone during senescence and identifies histone H3.3 and its proteolytically processed forms as key regulators of OIS. Importantly, it provides the first evidence of a biological role for H3 tail cleavage in a mammalian system.

ISBN: 9781321642414Subjects--Topical Terms:

751006
Oncology.

Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form.
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245 1 0 $a Chromatin dynamics in senescence: a novel role for histone variant H3.3 and its proteolytically processed form.
300 $a 163 p.
500 $a Source: Dissertation Abstracts International, Volume: 76-08(E), Section: B.
500 $a Advisers: Emily Bernstein; James J. Manfredi.
502 $a Thesis (Ph.D.)--Icahn School of Medicine at Mount Sinai, 2015.
520 $a Oncogene-induced senescence (OIS) is characterized by irreversible loss of proliferative capacity. Senescence induction depends on the p53 and Rb signaling pathways, which cooperate to ensure cell cycle arrest. OIS functions as a tumor suppressor mechanism, and several studies have demonstrated induction of senescence markers in pre-malignant lesions. For example, melanocytes within human nevi often harbor an activating mutation in BRAF (BRAFV600E) and can remain senescent for decades. In addition to profound morphological changes, significant alterations in chromatin structure occur during senescence including formation of senescence-associated heterochromatin foci (SAHF). SAHFs are enriched in heterochromatic markers including H3K9me3 and the histone variant macroH2A. Further, there is a re-distribution of histone post-translational modifications (PTMs) in senescent cells, with global loss of euchromatic markers concomitant with enrichment of heterochromatin-inducing PTMs. While it is now well established that cellular senescence generates a repressive chromatin environment, the role of histone variants and histone modifications such as proteolytic cleavage remains unclear. Using models of oncogene-induced and replicative senescence, we identified novel histone H3 tail cleavage events mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and that the histone variant H3.3 is the preferred form. Cleavage of H3 tail has been described in other models including Tetrahymena micronuclei and differentiated mouse ES cells. However, no direct biological role for the cleaved form of histone H3 has been described. Here, we show that ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first twenty-one amino acids, is sufficient to induce senescence. Further, H3.3cs1 chromatin incorporation is mediated by the histone chaperone ASF1a, which has previously been shown to play an important role during OIS. Genome-wide transcriptional profiling indicates that H3 tail cleavage facilitates transcriptional silencing of cell cycle regulators including Rb/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, my study provides the first example of proteolytic processing of a histone during senescence and identifies histone H3.3 and its proteolytically processed forms as key regulators of OIS. Importantly, it provides the first evidence of a biological role for H3 tail cleavage in a mammalian system.
590 $a School code: 1734.
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650 4 $a Biochemistry. $3 518028
650 4 $a Molecular biology. $3 517296
650 4 $a Cellular biology. $3 3172791
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710 2 $a Icahn School of Medicine at Mount Sinai. $b Cancer Biology. $3 3182916
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