Page 7 - 2014 Printable Abstract Book
P. 7
Michael Fry Lecture
(AL02) Functions of SIRT2 in the Replication Stress Response
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Hui Zhang ; Yungeng Pan ; Xingzhe Li ; Seong-Hoon Park ; Duc M. Duong ; Maohua Xie ; Bing Yu ; Bing
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Yu ; Elaine A. Liu ; Xingming Deng ; Nicholas T. Seyfried ; David Gius ; David S. Yu, Department of
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Radiation Oncology, Emory University School of Medicine, Atlanta, GA ; Department of Radiation
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Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL ; and Department of
Biochemistry, Emory University School of Medicine, Atlanta, GA
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The role of the acetylome in regulating non-histone protein function in the Replication Stress
Response (RSR) is poorly understood. SIRT2 is a sirtuin family deacetylase that directs acetylome signaling,
protects genome integrity, and is a murine tumor suppressor. Here we show that SIRT2 directs the RSR
through deacetylation of a network of proteins involved in the RSR, including Ataxia Telangiectasia
Mutated and Rad3 Related (ATR) Interacting Protein (ATRIP), the regulatory partner of ATR. SIRT2
deficiency results in replication stress sensitivity including radiation sensitivity, impairment in recovery
from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, a G2/M
checkpoint deficit, and impairment in ATR dependent signaling. SIRT2 interacts in a complex with a
number of proteins involved in the RSR, including ATR-ATRIP, and deacetylates ATRIP in response to
replication stress. Site-specific ATRIP lysine deacetylation by SIRT2 promotes ATR-ATRIP recruitment to
RPA and consequent activation and signaling, thus facilitating recovery from replication stress. Our results
define a novel mechanism for the regulation of ATR-ATRIP through deacetylation by SIRT2 and provide
insight into how the SIRT2 acetylome directs the RSR and a unique mechanism by which SIRT2 may
function, at least in part, as a tumor suppressor protein.
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(AL02) Functions of SIRT2 in the Replication Stress Response
1
1
1
1
2
3
1
Hui Zhang ; Yungeng Pan ; Xingzhe Li ; Seong-Hoon Park ; Duc M. Duong ; Maohua Xie ; Bing Yu ; Bing
1
3
1
1
1
1
Yu ; Elaine A. Liu ; Xingming Deng ; Nicholas T. Seyfried ; David Gius ; David S. Yu, Department of
1
Radiation Oncology, Emory University School of Medicine, Atlanta, GA ; Department of Radiation
2
Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL ; and Department of
Biochemistry, Emory University School of Medicine, Atlanta, GA
3
The role of the acetylome in regulating non-histone protein function in the Replication Stress
Response (RSR) is poorly understood. SIRT2 is a sirtuin family deacetylase that directs acetylome signaling,
protects genome integrity, and is a murine tumor suppressor. Here we show that SIRT2 directs the RSR
through deacetylation of a network of proteins involved in the RSR, including Ataxia Telangiectasia
Mutated and Rad3 Related (ATR) Interacting Protein (ATRIP), the regulatory partner of ATR. SIRT2
deficiency results in replication stress sensitivity including radiation sensitivity, impairment in recovery
from replication arrest, spontaneous accumulation of replication protein A to foci and chromatin, a G2/M
checkpoint deficit, and impairment in ATR dependent signaling. SIRT2 interacts in a complex with a
number of proteins involved in the RSR, including ATR-ATRIP, and deacetylates ATRIP in response to
replication stress. Site-specific ATRIP lysine deacetylation by SIRT2 promotes ATR-ATRIP recruitment to
RPA and consequent activation and signaling, thus facilitating recovery from replication stress. Our results
define a novel mechanism for the regulation of ATR-ATRIP through deacetylation by SIRT2 and provide
insight into how the SIRT2 acetylome directs the RSR and a unique mechanism by which SIRT2 may
function, at least in part, as a tumor suppressor protein.
5 | P a g e
