Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis

Yong Sam Jung, Anne Hakem, Razqallah Hakem, Xinbin Chen

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Polymerase eta (PolH) is necessary for translesion DNA synthesis, and PolH deficiency predisposes xeroderma pigmentosum variant (XPV) patients to cancer. Due to the critical role of PolH in translesion DNA synthesis, the activity of PolH is tightly controlled and subjected to multiple regulations, especially posttranslational modifications. Here, we show that PolH-dependent lesion bypass and intracellular translocation are regulated by Pirh2 E3 ubiquitin ligase through monoubiquitination. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues. We also show that monoubiquitination of PolH inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions, leading to decreased viability of UV-damaged cells. Moreover, we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions. Considering that Pirh2 is known to be overexpressed in various cancers, we postulate that in addition to mutation of PolH in XPV patients, inactivation of PolH by Pirh2 via monoubiquitination is one of the mechanisms by which PolH function is controlled, which might be responsible for the development and progression of some spontaneous tumors wherein PolH is not found to be mutated.

Original languageEnglish (US)
Pages (from-to)3997-4006
Number of pages10
JournalMolecular and Cellular Biology
Volume31
Issue number19
DOIs
StatePublished - Oct 2011

Fingerprint

Ubiquitin-Protein Ligases
DNA
Neoplasms
Proliferating Cell Nuclear Antigen
Post Translational Protein Processing
Lysine
Mutation
Rad30 protein
Variant type Xeroderma pigmentosum

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. / Jung, Yong Sam; Hakem, Anne; Hakem, Razqallah; Chen, Xinbin.

In: Molecular and Cellular Biology, Vol. 31, No. 19, 10.2011, p. 3997-4006.

Research output: Contribution to journalArticle

Jung, Yong Sam ; Hakem, Anne ; Hakem, Razqallah ; Chen, Xinbin. / Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis. In: Molecular and Cellular Biology. 2011 ; Vol. 31, No. 19. pp. 3997-4006.
@article{d1adbf87f06a428bb05bf1d600b4a9e9,
title = "Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis",
abstract = "Polymerase eta (PolH) is necessary for translesion DNA synthesis, and PolH deficiency predisposes xeroderma pigmentosum variant (XPV) patients to cancer. Due to the critical role of PolH in translesion DNA synthesis, the activity of PolH is tightly controlled and subjected to multiple regulations, especially posttranslational modifications. Here, we show that PolH-dependent lesion bypass and intracellular translocation are regulated by Pirh2 E3 ubiquitin ligase through monoubiquitination. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues. We also show that monoubiquitination of PolH inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions, leading to decreased viability of UV-damaged cells. Moreover, we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions. Considering that Pirh2 is known to be overexpressed in various cancers, we postulate that in addition to mutation of PolH in XPV patients, inactivation of PolH by Pirh2 via monoubiquitination is one of the mechanisms by which PolH function is controlled, which might be responsible for the development and progression of some spontaneous tumors wherein PolH is not found to be mutated.",
author = "Jung, {Yong Sam} and Anne Hakem and Razqallah Hakem and Xinbin Chen",
year = "2011",
month = "10",
doi = "10.1128/MCB.05808-11",
language = "English (US)",
volume = "31",
pages = "3997--4006",
journal = "Molecular and Cellular Biology",
issn = "0270-7306",
publisher = "American Society for Microbiology",
number = "19",

}

TY - JOUR

T1 - Pirh2 E3 ubiquitin ligase monoubiquitinates DNA polymerase eta to suppress translesion DNA synthesis

AU - Jung, Yong Sam

AU - Hakem, Anne

AU - Hakem, Razqallah

AU - Chen, Xinbin

PY - 2011/10

Y1 - 2011/10

N2 - Polymerase eta (PolH) is necessary for translesion DNA synthesis, and PolH deficiency predisposes xeroderma pigmentosum variant (XPV) patients to cancer. Due to the critical role of PolH in translesion DNA synthesis, the activity of PolH is tightly controlled and subjected to multiple regulations, especially posttranslational modifications. Here, we show that PolH-dependent lesion bypass and intracellular translocation are regulated by Pirh2 E3 ubiquitin ligase through monoubiquitination. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues. We also show that monoubiquitination of PolH inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions, leading to decreased viability of UV-damaged cells. Moreover, we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions. Considering that Pirh2 is known to be overexpressed in various cancers, we postulate that in addition to mutation of PolH in XPV patients, inactivation of PolH by Pirh2 via monoubiquitination is one of the mechanisms by which PolH function is controlled, which might be responsible for the development and progression of some spontaneous tumors wherein PolH is not found to be mutated.

AB - Polymerase eta (PolH) is necessary for translesion DNA synthesis, and PolH deficiency predisposes xeroderma pigmentosum variant (XPV) patients to cancer. Due to the critical role of PolH in translesion DNA synthesis, the activity of PolH is tightly controlled and subjected to multiple regulations, especially posttranslational modifications. Here, we show that PolH-dependent lesion bypass and intracellular translocation are regulated by Pirh2 E3 ubiquitin ligase through monoubiquitination. Specifically, we show that Pirh2, a target of the p53 tumor suppressor, monoubiquitinates PolH at one of multiple lysine residues. We also show that monoubiquitination of PolH inhibits the ability of PolH to interact with PCNA and to bypass UV-induced lesions, leading to decreased viability of UV-damaged cells. Moreover, we show that monoubiquitination of PolH alters the ability of PolH to translocate to replication foci for translesion DNA synthesis of UV-induced DNA lesions. Considering that Pirh2 is known to be overexpressed in various cancers, we postulate that in addition to mutation of PolH in XPV patients, inactivation of PolH by Pirh2 via monoubiquitination is one of the mechanisms by which PolH function is controlled, which might be responsible for the development and progression of some spontaneous tumors wherein PolH is not found to be mutated.

UR - http://www.scopus.com/inward/record.url?scp=80053579178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053579178&partnerID=8YFLogxK

U2 - 10.1128/MCB.05808-11

DO - 10.1128/MCB.05808-11

M3 - Article

C2 - 21791603

AN - SCOPUS:80053579178

VL - 31

SP - 3997

EP - 4006

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

SN - 0270-7306

IS - 19

ER -