Recognition of double strand breaks by a mutator protein (MU2) in Drosophila melanogaster.
Recognition of double strand breaks by a mutator protein (MU2) in Drosophila melanogaster.
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DOI：
10.1371/journal.pgen.1000473
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发表时间：
2009-05
期刊：
影响因子：
4.5
通讯作者：
Mason JM
中科院分区：
文献类型：
--
作者：
Dronamraju R;Mason JM
Telomere capture, a rare event that stabilizes chromosome breaks, is associated with certain genetic abnormalities in humans. Studies pertaining to the generation, maintenance, and biological effects of telomere formation are limited in metazoans. A mutation, mu2a, in Drosophila melanogaster decreases the rate of repair of double strand DNA breaks in oocytes, thus leading to chromosomes that have lost a natural telomere and gained a new telomere. Amino acid sequence, domain architecture, and protein interactions suggest that MU2 is an ortholog of human MDC1. The MU2 protein is a component of meiotic recombination foci and localizes to repair foci in S2 cells after irradiation in a manner similar to that of phosphorylated histone variant H2Av. Domain searches indicated that the protein contains an N-terminal FHA domain and a C-terminal tandem BRCT domain. Peptide pull-down studies showed that the BRCT domain interacts with phosphorylated H2Av, while the FHA domain interacts with the complex of MRE11, RAD50, and NBS. A frameshift mutation that eliminates the MU2 BRCT domain decreases the number and size of meiotic phospho-H2Av foci. MU2 is also required for the intra-S checkpoint in eye-antennal imaginal discs. MU2 participates at an early stage in the recognition of DNA damage at a step that is prerequisite for both DNA repair and cell cycle checkpoint control. We propose a model suggesting that neotelomeres may arise when radiation-induced chromosome breaks fail to be repaired, fail to arrest progression through meiosis, and are deposited in the zygote, where cell cycle control is absent and rapid rounds of replication and telomere formation ensue. Telomeres are structures at the ends of eukaryotic chromosomes required for chromosome stability. If unrepaired, a single chromosome end without a telomere is sufficient to kill a cell, but new telomere formation is rare. Previously, we described a gene in Drosophila whose mutants, after irradiation, produced many progeny with chromosomes lacking a natural telomere. The new broken chromosome ends, however, bound telomeric proteins and behaved as telomeres. Here, we show that the protein encoded by this gene, a homolog of the human MDC1 gene, is a component of the repair foci that form at double strand DNA breaks and are prerequisite for both cell cycle arrest and DNA repair. The protein acts as a scaffold, connecting a phosphorylated histone that marks the site of the break to a protein complex necessary for repair. These results suggest a model for formation of neotelomeres in which DNA breaks induced in mutant oocytes evade repair and are deposited into embryos, which contain an abundance of maternally deposited telomeric proteins. In this context a chromosome end not recognized as broken may be treated as a telomere. These results may provide a basis to understand neotelomere formation.
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影响因子：
16
作者：
Lou, ZK;Minter-Dykhouse, K;Chen, JJ
通讯作者：
Chen, JJ
DOI：
10.1073/pnas.110149597
发表时间：
2000-06-06
影响因子：
11.1
作者：
Clemens, JC;Worby, CA;Dixon, JE
通讯作者：
Dixon, JE
DOI：
10.1016/0027-5107(79)90107-6
发表时间：
1979-01-01
期刊：
MUTATION RESEARCH
影响因子：
--
作者：
GRAF, U;GREEN, MM;WURGLER, FE
通讯作者：
WURGLER, FE
DOI：
10.1073/pnas.81.19.6090
发表时间：
1984-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
MASON, JM;STROBEL, E;GREEN, MM
通讯作者：
GREEN, MM
影响因子：
4.8
作者：
Hematulin, Arunee;Sagan, Daniel;Moertl, Simone
通讯作者：
Moertl, Simone