DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation

Yong Sam Jung, Yingjuan Qian, Xinbin Chen

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination. in vivo and. in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.

Original languageEnglish (US)
Pages (from-to)177-184
Number of pages8
JournalDNA Repair
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2012

Fingerprint

Ubiquitin-Protein Ligases
Irradiation
Degradation
Proteasome Inhibitors
Skin Neoplasms
DNA-Directed DNA Polymerase
Skin
Carcinogenesis
Genes
DNA
Rad30 protein
Neoplasms
Variant type Xeroderma pigmentosum
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
In Vitro Techniques

Keywords

  • E3 ligase
  • Mdm2
  • PolH
  • Ubiquitination
  • UV

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation. / Jung, Yong Sam; Qian, Yingjuan; Chen, Xinbin.

In: DNA Repair, Vol. 11, No. 2, 01.02.2012, p. 177-184.

Research output: Contribution to journalArticle

@article{713b3d5140d44b87938c46719689072e,
title = "DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation",
abstract = "DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination. in vivo and. in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.",
keywords = "E3 ligase, Mdm2, PolH, Ubiquitination, UV",
author = "Jung, {Yong Sam} and Yingjuan Qian and Xinbin Chen",
year = "2012",
month = "2",
day = "1",
doi = "10.1016/j.dnarep.2011.10.017",
language = "English (US)",
volume = "11",
pages = "177--184",
journal = "DNA Repair",
issn = "1568-7864",
publisher = "Elsevier",
number = "2",

}

TY - JOUR

T1 - DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation

AU - Jung, Yong Sam

AU - Qian, Yingjuan

AU - Chen, Xinbin

PY - 2012/2/1

Y1 - 2012/2/1

N2 - DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination. in vivo and. in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.

AB - DNA polymerase eta (PolH), the product of the xeroderma pigmentosum variant (XPV) gene and a Y-family DNA polymerase, plays a pivotal role in translesion DNA synthesis. Loss of PolH leads to early onset of malignant skin cancer in XPV patients and increases UV-induced carcinogenesis. Thus, the pathways by which PolH expression and activity are controlled may be explored as a strategy to prevent UV-induced cancer. In this study, we found that Mdm2, a RING finger E3 ligase, promotes PolH degradation. Specifically, we showed that knockdown of Mdm2 increases PolH expression in both p53-proficient and -deficient cells. In addition, we showed that UV-induced PolH degradation is attenuated by Mdm2 knockdown. In contrast, ectopically expression of Mdm2 decreases PolH expression, which can be abrogated by the proteasome inhibitor MG132. Moreover, we showed that Mdm2 physically associates with PolH and promotes PolH polyubiquitination. in vivo and. in vitro. Finally, we showed that knockdown of Mdm2 increases the formation of PolH replication foci and decreases the sensitivity of cells to UV-induced lesions in a PolH-dependent manner. Taken together, we uncovered that Mdm2 serves as an E3 ligase for PolH polyubiquitination and proteasomal degradation in cells under the basal condition and in response to UV irradiation.

KW - E3 ligase

KW - Mdm2

KW - PolH

KW - Ubiquitination

KW - UV

UR - http://www.scopus.com/inward/record.url?scp=84855850825&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84855850825&partnerID=8YFLogxK

U2 - 10.1016/j.dnarep.2011.10.017

DO - 10.1016/j.dnarep.2011.10.017

M3 - Article

VL - 11

SP - 177

EP - 184

JO - DNA Repair

JF - DNA Repair

SN - 1568-7864

IS - 2

ER -