WRN participates in translesion synthesis pathway through interaction with NBS1

Junya Kobayashi, Michiyo Okui, Aroumougame Asaithamby, Sandeep Burma, Benjamin P C Chen, Keiji Tanimoto, Shinya Matsuura, Kenshi Komatsu, David J. Chen

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Werner syndrome (WS), caused by mutation of the WRN gene, is an autosomal recessive disorder associated with premature aging and predisposition to cancer. WRN belongs to the RecQ DNA helicase family, members of which play a role in maintaining genomic stability. Here, we demonstrate that WRN rapidly forms discrete nuclear foci in an NBS1-dependent manner following DNA damage. NBS1 physically interacts with WRN through its FHA domain, which interaction is important for the phosphorylation of WRN. WRN subsequently forms DNA damage-dependent foci during the S phase, but not in the G1 phase. WS cells exhibit an increase in spontaneous focus formation of polη and Rad18, which are important for translesion synthesis (TLS). WRN also interacts with PCNA in the absence of DNA damage, but DNA damage induces the dissociation of PCNA from WRN, leading to the ubiquitination of PCNA, which is essential for TLS. This dissociation correlates with ATM/NBS1-dependent degradation of WRN. Moreover, WS cells show constitutive ubiquitination of PCNA and interaction between PCNA and Rad18 E3 ligase in the absence of DNA damage. Taken together, these results indicate that WRN participates in the TLS pathway to prevent genomic instability in an ATM/NBS1-dependent manner.

Original languageEnglish (US)
Pages (from-to)436-444
Number of pages9
JournalMechanisms of Ageing and Development
Volume131
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Proliferating Cell Nuclear Antigen
DNA Damage
Werner Syndrome
Genomic Instability
Ubiquitination
RecQ Helicases
DNA Helicases
Premature Aging
Ubiquitin-Protein Ligases
G1 Phase
S Phase
Phosphorylation
Mutation
Genes
Neoplasms

Keywords

  • NBS1
  • PCNA
  • Rad18
  • TLS
  • WRN

ASJC Scopus subject areas

  • Aging
  • Developmental Biology
  • Medicine(all)

Cite this

WRN participates in translesion synthesis pathway through interaction with NBS1. / Kobayashi, Junya; Okui, Michiyo; Asaithamby, Aroumougame; Burma, Sandeep; Chen, Benjamin P C; Tanimoto, Keiji; Matsuura, Shinya; Komatsu, Kenshi; Chen, David J.

In: Mechanisms of Ageing and Development, Vol. 131, No. 6, 06.2010, p. 436-444.

Research output: Contribution to journalArticle

Kobayashi, Junya ; Okui, Michiyo ; Asaithamby, Aroumougame ; Burma, Sandeep ; Chen, Benjamin P C ; Tanimoto, Keiji ; Matsuura, Shinya ; Komatsu, Kenshi ; Chen, David J. / WRN participates in translesion synthesis pathway through interaction with NBS1. In: Mechanisms of Ageing and Development. 2010 ; Vol. 131, No. 6. pp. 436-444.
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