Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein

Sankar Mitra; Tadahide Izumi; Istvan Boldogh; Kishor K. Bhakat; Ranajoy Chattopadhyay; Bartosz Szczesny

doi:10.1016/j.dnarep.2006.10.010

Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein

Sankar Mitra, Tadahide Izumi, Istvan Boldogh, Kishor K. Bhakat, Ranajoy Chattopadhyay, Bartosz Szczesny

Toxicology and Cancer Biology

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

Abstract

AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct APEs of Xth and Nfo types, mammalian genomes encode only one APE, APE1, which is of the Xth type. However, while the APEs together are dispensable in the bacteria and simple eukaryotes, APE1 is essential for mammalian cells. We have shown that apoptosis of mouse embryo fibroblasts triggered by APE1 inactivation can be prevented by ectopic expression of repair competent but not repair-defective APE1. The mitochondrial APE (mtAPE) is an N-terminal truncation product of APE1. A significant fraction of APE1 is cytosolic, and oxidative stress induces its nuclear and mitochondrial translocation. Such age-dependent increase in APE activity in the nucleus and mitochondria is consistent with the hypothesis that aging is associated with chronic oxidative stress.

Original language	English
Pages (from-to)	461-469
Number of pages	9
Journal	DNA Repair
Volume	6
Issue number	4
DOIs	https://doi.org/10.1016/j.dnarep.2006.10.010
State	Published - Apr 1 2007

Bibliographical note

Funding Information:
The original research described in this review was supported by USPHS R01 ES08457, R01 CA53791 (SM), P30 ES06676, P01 AG-21803 (IB, SM), R01 CA98664 (TI). We express our sincere gratitude to Xiao-Feng Qin (M.D. Anderson Cancer Center, Houston, TX) for providing the lentiviral vector and critical guidance for generating recombinant lentiviruses. We also thank Wanda Smith for expert secretarial assistance and UTMB Cell Sorting Facility for FACS analysis.

Funding

The original research described in this review was supported by USPHS R01 ES08457, R01 CA53791 (SM), P30 ES06676, P01 AG-21803 (IB, SM), R01 CA98664 (TI). We express our sincere gratitude to Xiao-Feng Qin (M.D. Anderson Cancer Center, Houston, TX) for providing the lentiviral vector and critical guidance for generating recombinant lentiviruses. We also thank Wanda Smith for expert secretarial assistance and UTMB Cell Sorting Facility for FACS analysis.

Funders	Funder number
National Institute on Aging	P01AG021830
U.S. Public Health Service	R01 CA53791, R01 CA98664, R01 ES08457, P01 AG-21803, P30 ES06676

Keywords

Age-dependent repair activity
Mitochondrial APE
Nuclear export signal
Spontaneous AP sites

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

Access to Document

10.1016/j.dnarep.2006.10.010

Cite this

@article{20aaafbaf3ed48dd90f4cdef90cb2dbe,

title = "Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein",

abstract = "AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct APEs of Xth and Nfo types, mammalian genomes encode only one APE, APE1, which is of the Xth type. However, while the APEs together are dispensable in the bacteria and simple eukaryotes, APE1 is essential for mammalian cells. We have shown that apoptosis of mouse embryo fibroblasts triggered by APE1 inactivation can be prevented by ectopic expression of repair competent but not repair-defective APE1. The mitochondrial APE (mtAPE) is an N-terminal truncation product of APE1. A significant fraction of APE1 is cytosolic, and oxidative stress induces its nuclear and mitochondrial translocation. Such age-dependent increase in APE activity in the nucleus and mitochondria is consistent with the hypothesis that aging is associated with chronic oxidative stress.",

keywords = "Age-dependent repair activity, Mitochondrial APE, Nuclear export signal, Spontaneous AP sites",

author = "Sankar Mitra and Tadahide Izumi and Istvan Boldogh and Bhakat, {Kishor K.} and Ranajoy Chattopadhyay and Bartosz Szczesny",

note = "Funding Information: The original research described in this review was supported by USPHS R01 ES08457, R01 CA53791 (SM), P30 ES06676, P01 AG-21803 (IB, SM), R01 CA98664 (TI). We express our sincere gratitude to Xiao-Feng Qin (M.D. Anderson Cancer Center, Houston, TX) for providing the lentiviral vector and critical guidance for generating recombinant lentiviruses. We also thank Wanda Smith for expert secretarial assistance and UTMB Cell Sorting Facility for FACS analysis.",

year = "2007",

month = apr,

day = "1",

doi = "10.1016/j.dnarep.2006.10.010",

language = "English",

volume = "6",

pages = "461--469",

number = "4",

}

TY - JOUR

T1 - Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein

AU - Mitra, Sankar

AU - Izumi, Tadahide

AU - Boldogh, Istvan

AU - Bhakat, Kishor K.

AU - Chattopadhyay, Ranajoy

AU - Szczesny, Bartosz

N1 - Funding Information: The original research described in this review was supported by USPHS R01 ES08457, R01 CA53791 (SM), P30 ES06676, P01 AG-21803 (IB, SM), R01 CA98664 (TI). We express our sincere gratitude to Xiao-Feng Qin (M.D. Anderson Cancer Center, Houston, TX) for providing the lentiviral vector and critical guidance for generating recombinant lentiviruses. We also thank Wanda Smith for expert secretarial assistance and UTMB Cell Sorting Facility for FACS analysis.

PY - 2007/4/1

Y1 - 2007/4/1

N2 - AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct APEs of Xth and Nfo types, mammalian genomes encode only one APE, APE1, which is of the Xth type. However, while the APEs together are dispensable in the bacteria and simple eukaryotes, APE1 is essential for mammalian cells. We have shown that apoptosis of mouse embryo fibroblasts triggered by APE1 inactivation can be prevented by ectopic expression of repair competent but not repair-defective APE1. The mitochondrial APE (mtAPE) is an N-terminal truncation product of APE1. A significant fraction of APE1 is cytosolic, and oxidative stress induces its nuclear and mitochondrial translocation. Such age-dependent increase in APE activity in the nucleus and mitochondria is consistent with the hypothesis that aging is associated with chronic oxidative stress.

AB - AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct APEs of Xth and Nfo types, mammalian genomes encode only one APE, APE1, which is of the Xth type. However, while the APEs together are dispensable in the bacteria and simple eukaryotes, APE1 is essential for mammalian cells. We have shown that apoptosis of mouse embryo fibroblasts triggered by APE1 inactivation can be prevented by ectopic expression of repair competent but not repair-defective APE1. The mitochondrial APE (mtAPE) is an N-terminal truncation product of APE1. A significant fraction of APE1 is cytosolic, and oxidative stress induces its nuclear and mitochondrial translocation. Such age-dependent increase in APE activity in the nucleus and mitochondria is consistent with the hypothesis that aging is associated with chronic oxidative stress.

KW - Age-dependent repair activity

KW - Mitochondrial APE

KW - Nuclear export signal

KW - Spontaneous AP sites

UR - http://www.scopus.com/inward/record.url?scp=33847666362&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33847666362&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2006.10.010

DO - 10.1016/j.dnarep.2006.10.010

M3 - Article

C2 - 17166779

AN - SCOPUS:33847666362

SN - 1568-7864

VL - 6

SP - 461

EP - 469

JO - DNA Repair

JF - DNA Repair

IS - 4

ER -

Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this