WRN regulates pathway choice between classical and alternative non-homologous end joining

Raghavendra A. Shamanna, Huiming Lu, Jessica K. De Freitas, Jane Tian, Deborah L. Croteau, Vilhelm A. Bohr

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions. When WRN is recruited to the DSBs it suppresses the recruitment of MRE11 and CtIP, and protects the DSBs from 5′ end resection. Moreover, knockdown of Wrn, alone or in combination with Trf2 in mouse embryonic fibroblasts results in increased telomere fusions, which were ablated by Ctip knockdown. We show that WRN regulates alt-NHEJ and shields DSBs from MRE11/CtIP-mediated resection to prevent large deletions and telomere fusions.

Original languageEnglish (US)
Article number13785
JournalNature Communications
Volume7
DOIs
StatePublished - Dec 6 2016
Externally publishedYes

Fingerprint

telomeres
Telomere
Joining
Werner Syndrome
deletion
Fusion reactions
fusion
DNA End-Joining Repair
Protein Deficiency
Exonucleases
Double-Stranded DNA Breaks
deoxyribonucleic acid
Genomic Instability
DNA
fibroblasts
metabolism
Fibroblasts
Metabolism
strands
mice

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

WRN regulates pathway choice between classical and alternative non-homologous end joining. / Shamanna, Raghavendra A.; Lu, Huiming; De Freitas, Jessica K.; Tian, Jane; Croteau, Deborah L.; Bohr, Vilhelm A.

In: Nature Communications, Vol. 7, 13785, 06.12.2016.

Research output: Contribution to journalArticle

Shamanna, Raghavendra A. ; Lu, Huiming ; De Freitas, Jessica K. ; Tian, Jane ; Croteau, Deborah L. ; Bohr, Vilhelm A. / WRN regulates pathway choice between classical and alternative non-homologous end joining. In: Nature Communications. 2016 ; Vol. 7.
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