Apollo Contributes to G Overhang Maintenance and Protects Leading-End Telomeres
Mammalian telomeres contain a single-stranded 3′ overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated...
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Published in | Molecular cell Vol. 39; no. 4; pp. 606 - 617 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
27.08.2010
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Subjects | |
Online Access | Get full text |
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Summary: | Mammalian telomeres contain a single-stranded 3′ overhang that is thought to mediate telomere protection. Here we identify the TRF2-interacting factor Apollo as a nuclease that contributes to the generation/maintenance of this overhang. The function of mouse Apollo was determined using Cre-mediated gene deletion, complementation with Apollo mutants, and the TRF2-F120A mutant that cannot bind Apollo. Cells lacking Apollo activated the ATM kinase at their telomeres in S phase and showed leading-end telomere fusions. These telomere dysfunction phenotypes were accompanied by a reduction in the telomeric overhang signal. The telomeric functions of Apollo required its TRF2-interaction and nuclease motifs. Thus, TRF2 recruits the Apollo nuclease to process telomere ends synthesized by leading-strand DNA synthesis, thereby creating a terminal structure that avoids ATM activation and resists end-joining. These data establish that the telomeric overhang is required for the protection of telomeres from the DNA damage response.
► The shelterin-associated Apollo/SNM1B nuclease was removed from mouse telomeres ► Apollo removal diminished the 3′ overhang and activated the ATM kinase in S phase ► Without Apollo, telomeres generated by leading-strand synthesis underwent fusions ► Thus, shelterin recruits Apollo to protect newly synthesized leading-end telomeres |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 Present address: Health Science Communications, 711 Third Avenue, New York, NY 10017. SRooney@health-ny.com. Present address: Department of Molecular Biology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. vanoverm@mskcc.org contributed equally. |
ISSN: | 1097-2765 1097-4164 |
DOI: | 10.1016/j.molcel.2010.06.031 |