RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells.
RNF4 and PLK1 are required for replication fork collapse in ATR-deficient cells.
复制标题
DOI：
10.1101/gad.223180.113
复制
发表时间：
2013-10-15
影响因子：
10.5
通讯作者：
Brown EJ
中科院分区：
文献类型：
--
作者：
Ragland RL;Patel S;Rivard RS;Smith K;Peters AA;Bielinsky AK;Brown EJ
The ATR–CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, Ragland et al. show that fork collapse in Atr-deleted cells is mediated through the combined effects of the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA–PLK1 pathway. DSB generation is also shown to be dependent on the SLX4–endonuclease complex. The results indicate that replication fork collapse following ATR inhibition is an active and multistep process necessary for the cleavage of the replication fork into DSBs. The ATR–CHK1 axis stabilizes stalled replication forks and prevents their collapse into DNA double-strand breaks (DSBs). Here, we show that fork collapse in Atr-deleted cells is mediated through the combined effects the sumo targeted E3-ubiquitin ligase RNF4 and activation of the AURKA–PLK1 pathway. As indicated previously, Atr-deleted cells exhibited a decreased ability to restart DNA replication following fork stalling in comparison with control cells. However, suppression of RNF4, AURKA, or PLK1 returned the reinitiation of replication in Atr-deleted cells to near wild-type levels. In RNF4-depleted cells, this rescue directly correlated with the persistence of sumoylation of chromatin-bound factors. Notably, RNF4 repression substantially suppressed the accumulation of DSBs in ATR-deficient cells, and this decrease in breaks was enhanced by concomitant inhibition of PLK1. DSBs resulting from ATR inhibition were also observed to be dependent on the endonuclease scaffold protein SLX4, suggesting that RNF4 and PLK1 either help activate the SLX4 complex or make DNA replication fork structures accessible for subsequent SLX4-dependent cleavage. Thus, replication fork collapse following ATR inhibition is a multistep process that disrupts replisome function and permits cleavage of the replication fork.
登录
查看更多内容
影响因子：
11.2
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
通讯作者：
Brown EJ
影响因子：
4.5
作者：
Holloway JK;Mohan S;Balmus G;Sun X;Modzelewski A;Borst PL;Freire R;Weiss RS;Cohen PE
通讯作者：
Cohen PE
影响因子：
64.8
作者：
Lopes, M;Cotta-Ramusino, C;Foiani, M
通讯作者：
Foiani, M
影响因子：
10.5
作者：
Galanty, Yaron;Belotserkovskaya, Rimma;Jackson, Stephen P.
通讯作者：
Jackson, Stephen P.
影响因子：
64.8
作者：
Macurek, Libor;Lindqvist, Arne;Medema, Rene H.
通讯作者：
Medema, Rene H.