Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks.
Human RNF169 is a negative regulator of the ubiquitin-dependent response to DNA double-strand breaks.
复制标题
DOI：
10.1083/jcb.201109100
复制
发表时间：
2012-04-16
期刊：
影响因子：
--
通讯作者：
Mailand N
中科院分区：
文献类型：
--
作者：
Poulsen M;Lukas C;Lukas J;Bekker-Jensen S;Mailand N
RNF 169与修复因子竞争结合DNA损伤位点的泛素化染色质，影响修复途径的利用。由RNF 8/RNF 168遍在蛋白连接酶介导的脱氧核糖核酸双链断裂（DSB）周围染色质的非蛋白水解遍在化在招募修复因子（包括53 BP 1和BRCA 1）以重建基因组完整性方面发挥着关键作用。在本文中，我们表明，人RNF 169，一个未表征的E3泛素连接酶旁系同源RNF 168，积累在DSB修复灶通过识别RNF 168催化的泛素化产物，其基序与泛素结构域相互作用。出乎意料的是，RNF 169是染色质泛素化和泛素依赖的修复因子在DSB位点的积累。相反，RNF 169在功能上与53 BP 1和RAP 80-BRCA 1竞争与RNF 168修饰的染色质的结合，而不依赖于其催化活性，限制了它们募集到DSB位点的幅度。通过延迟53 BP 1和RAP 80在受损染色质处的积累，RNF 169刺激同源重组并抑制非同源末端连接，从而影响DSB施加后的细胞存活。我们的研究结果表明，RNF 169的功能在一个非经典的方式利用RNF 168介导的蛋白质招募到含有DSB的染色质，从而有助于调节DSB修复途径的利用。
RNF169 competes with repair factors to bind to ubiquitylated chromatin at sites of DNA damage, influencing repair pathway utilization. Nonproteolytic ubiquitylation of chromatin surrounding deoxyribonucleic acid double-strand breaks (DSBs), mediated by the RNF8/RNF168 ubiquitin ligases, plays a key role in recruiting repair factors, including 53BP1 and BRCA1, to reestablish genome integrity. In this paper, we show that human RNF169, an uncharacterized E3 ubiquitin ligase paralogous to RNF168, accumulated in DSB repair foci through recognition of RNF168-catalyzed ubiquitylation products by its motif interacting with ubiquitin domain. Unexpectedly, RNF169 was dispensable for chromatin ubiquitylation and ubiquitin-dependent accumulation of repair factors at DSB sites. Instead, RNF169 functionally competed with 53BP1 and RAP80–BRCA1 for association with RNF168-modified chromatin independent of its catalytic activity, limiting the magnitude of their recruitment to DSB sites. By delaying accumulation of 53BP1 and RAP80 at damaged chromatin, RNF169 stimulated homologous recombination and restrained nonhomologous end joining, affecting cell survival after DSB infliction. Our results show that RNF169 functions in a noncanonical fashion to harness RNF168-mediated protein recruitment to DSB-containing chromatin, thereby contributing to regulation of DSB repair pathway utilization.
登录
查看更多内容
DOI：
10.1083/jcb.200510130
发表时间：
2006-04-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bekker-Jensen S;Lukas C;Kitagawa R;Melander F;Kastan MB;Bartek J;Lukas J
通讯作者：
Lukas J
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
56.9
作者：
Kim, Hongtae;Chen, Junjie;Yu, Xiaochun
通讯作者：
Yu, Xiaochun
影响因子：
16
作者：
Ciccia A;Elledge SJ
通讯作者：
Elledge SJ
影响因子：
64.8
作者：
Morris, Joanna R.;Boutell, Chris;Solomon, Ellen
通讯作者：
Solomon, Ellen