Suppression of gross chromosomal rearrangements by yKu70-yKu80 heterodimer through DNA damage checkpoints

被引:12
作者
Banerjee, S [1 ]
Smith, S [1 ]
Myung, K [1 ]
机构
[1] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA
关键词
cancer; DNA repair;
D O I
10.1073/pnas.0504063102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The inactivation of either subunit of the Ku70-Ku80 heterodimer, which functions in nonhomologous end-joining and telomere maintenance, generates severe defects such as sensitivity to DNA damage, telomere shortening, and increased gross chromosomal rearrangements (GCRs) that are frequently observed in many cancers. To understand the mechanism of Ku as a genome gatekeeper, we overexpressed the yKu70-yKu80 heterodimer and monitored the formation of GCRs. Ku overexpression suppressed the formation of either spontaneously generated GCRs or those induced by treatments with different DNA damaging agents. Interestingly, this suppression depended on Ku's interaction with DNA damage checkpoints and not through nonhomologous end-joining. We also demonstrate that the inactivation of telomerase inhibitor, Pif1 along with Ku overexpression or the over expression of Pif1 in either yku70 or yku80 strains arrested the cell cycle at S phase in a DNA damage checkpoint-dependent fashion. Lastly, Ku overexpression causes cell growth delay, which depends on intact Rad27. In summary, the results presented here suggest that Ku functions as a genomic gatekeeper through its crosstalk with DNA damage checkpoints.
引用
收藏
页码:1816 / 1821
页数:6
相关论文
共 65 条
[51]   Regulation of DNA-replication origins during cell-cycle progression [J].
Shirahige, K ;
Hori, Y ;
Shiraishi, K ;
Yamashita, M ;
Takahashi, K ;
Obuse, C ;
Tsurimoto, T ;
Yoshikawa, H .
NATURE, 1998, 395 (6702) :618-621
[52]  
Shor E, 2002, GENETICS, V162, P647
[53]   Mutator genes for suppression of gross chromosomal rearrangements identified by a genome-wide screening in Saccharomyces cerevisiae [J].
Smith, S ;
Hwang, JY ;
Banerjee, S ;
Majeed, A ;
Gupta, A ;
Myung, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (24) :9039-9044
[54]   Suppression of gross chromosomal rearrangements by the multiple functions of the Mre11-Rad50-Xrs2 complex in Saccharomyces cerevisiae [J].
Smith, S ;
Gupta, A ;
Kolodner, RD ;
Myung, K .
DNA REPAIR, 2005, 4 (05) :606-617
[55]   ELG1, a regulator of genome stability, has a role in telomere length regulation and in silencing [J].
Smolikov, S ;
Mazor, Y ;
Krauskopf, A .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (06) :1656-1661
[56]   Role of RAD52 epistasis group genes in homologous recombination and double-strand break repair [J].
Symington, LS .
MICROBIOLOGY AND MOLECULAR BIOLOGY REVIEWS, 2002, 66 (04) :630-+
[57]   Deregulated G1-cyclin expression induces genomic instability by preventing efficient pre-RC formation [J].
Tanaka, S ;
Diffley, JFX .
GENES & DEVELOPMENT, 2002, 16 (20) :2639-2649
[58]   A novel mutation avoidance mechanism dependent on S-cerevisiae RAD27 is distinct from DNA mismatch repair [J].
Tishkoff, DX ;
Filosi, N ;
Gaida, GM ;
Kolodner, RD .
CELL, 1997, 88 (02) :253-263
[59]   Dual functional regulators coordinate DNA replication and gene expression in proliferating cells [J].
Tye, BK ;
Chang, VK .
FRONTIERS IN BIOSCIENCE-LANDMARK, 2004, 9 :2548-2555
[60]  
Umezu K, 1998, GENETICS, V148, P989