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 language | English (US) |
|---|---|
| Article number | 13785 |
| Journal | Nature Communications |
| Volume | 7 |
| DOIs | |
| State | Published - Dec 6 2016 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - WRN regulates pathway choice between classical and alternative non-homologous end joining
AU - Shamanna, Raghavendra A.
AU - Lu, Huiming
AU - De Freitas, Jessica K.
AU - Tian, Jane
AU - Croteau, Deborah L.
AU - Bohr, Vilhelm A.
PY - 2016/12/6
Y1 - 2016/12/6
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85002709887&partnerID=8YFLogxK
U2 - 10.1038/ncomms13785
DO - 10.1038/ncomms13785
M3 - Article
C2 - 27922005
AN - SCOPUS:85002709887
VL - 7
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 13785
ER -