Replicon Dynamics, Dormant Origin Firing, and Terminal Fork Integrity after Double-Strand Break Formation

被引:87
作者
Doksani, Ylli [1 ,2 ]
Bermejo, Rodrigo [1 ,2 ]
Fiorani, Simona [1 ,2 ]
Haber, James E. [3 ,4 ]
Foiani, Marco [1 ,2 ]
机构
[1] Univ Milan, FIRC Inst Mol Oncol Fdn, IFOM, IEO Campus, I-20139 Milan, Italy
[2] Univ Milan, DSBB, I-20139 Milan, Italy
[3] Brandeis Univ, Rosenstiel Ctr, Waltham, MA 02254 USA
[4] Brandeis Univ, Dept Biol, Waltham, MA 02254 USA
基金
美国国家卫生研究院;
关键词
DNA-DAMAGE RESPONSE; STALLED REPLICATION FORKS; HUMAN-CELLS; CHECKPOINT ACTIVATION; GENOMIC INSTABILITY; CHROMOSOME-III; YEAST; ATR; COMPLEX; ARREST;
D O I
10.1016/j.cell.2009.02.016
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In response to replication stress, the Mec1/ATR and SUMO pathways control stalled-and damaged-fork stability. We investigated the S phase response at forks encountering a broken template (termed the terminal fork). We show that double-strand break (DSB) formation can locally trigger dormant origin firing. Irreversible fork resolution at the break does not impede progression of the other fork in the same replicon (termed the sister fork). The Mre11-Tel1/ATM response acts at terminal forks, preventing accumulation of cruciform DNA intermediates that tether sister chromatids and can undergo nucleolytic processing. We conclude that sister forks can be uncoupled during replication and that, after DSB-induced fork termination, replication is rescued by dormant origin firing or adjacent replicons. We have uncovered a Tel1/ATM- and Mre11-dependent response controlling terminal fork integrity. Our findings have implications for those genome instability syndromes that accumulate DNA breaks during S phase and for forks encountering eroding telomeres.
引用
收藏
页码:247 / 258
页数:12
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