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PMID: 20588252 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

The function of classical and alternative non-homologous end-joining pathways in the fusion of dysfunctional telomeres.

The EMBO journal ·Vol. 29 ·No. 15 ·2010-08-04 ·Pages 2598-610

Rai R, Zheng H, He H, Luo Y, Multani A, Carpenter PB, Chang S

Abstract

Repair of DNA double-stranded breaks (DSBs) is crucial for the maintenance of genome stability. DSBs are repaired by either error prone non-homologous end-joining (NHEJ) or error-free homologous recombination. NHEJ precedes either by a classic, Lig4-dependent process (C-NHEJ) or an alternative, Lig4-independent one (A-NHEJ). Dysfunctional telomeres arising either through natural attrition due to telomerase deficiency or by removal of telomere-binding proteins are recognized as DSBs. In this report, we studied which end-joining pathways are required to join dysfunctional telomeres. In agreement with earlier studies, depletion of Trf2 resulted in end-to-end chromosome fusions mediated by the C-NHEJ pathway. In contrast, removal of Tpp1-Pot1a/b initiated robust chromosome fusions that are mediated by A-NHEJ. C-NHEJ is also dispensable for the fusion of naturally shortened telomeres. Our results reveal that telomeres engage distinct DNA repair pathways depending on how they are rendered dysfunctional, and that A-NHEJ is a major pathway to process dysfunctional telomeres.

MeSH Terms
Animals Antigens, Nuclear/metabolism Cells, Cultured Chromosomal Proteins, Non-Histone DNA Repair DNA-Binding Proteins/deficiency,metabolism Humans Intracellular Signaling Peptides and Proteins/deficiency,genetics,metabolism Ku Autoantigen Mice Mice, Knockout Telomere Telomeric Repeat Binding Protein 2/metabolism Tripeptidyl-Peptidase 1 Tumor Suppressor p53-Binding Protein 1
Chemicals
Antigens, Nuclear Chromosomal Proteins, Non-Histone DNA-Binding Proteins Intracellular Signaling Peptides and Proteins TRF2 protein, mouse Telomeric Repeat Binding Protein 2 Tpp1 protein, mouse Tripeptidyl-Peptidase 1 Trp53bp1 protein, mouse Tumor Suppressor p53-Binding Protein 1 TPP1 protein, human Xrcc6 protein, human Xrcc6 protein, mouse Ku Autoantigen
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Rai Rekha
Department of Genetics, MD Anderson Cancer Center, Houston, TX, USA.
Zheng Hong
He Hua
Luo Ying
Multani Asha
Carpenter Phillip B
Chang Sandy
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2010.142
Published
2010-08-04
Epub
2010-00-29
Pages
2598-610
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2928694
Subset
IM
Grants
NIA NIH HHS · R01 AG028888 · United States
NCI NIH HHS · R01 CA129037 · United States
NIAID NIH HHS · R21 AI076747 · United States
NIAID NIH HHS · 5R21-AI076747-01 · United States
External Links
PubMed source DOI: 10.1038/emboj.2010.142 PMC Full Text View journal details
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