Replication stress induces accumulation of FANCD2 at central region of large fragile genes.
Replication stress induces accumulation of FANCD2 at central region of large fragile genes.
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DOI：
10.1093/nar/gky058
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发表时间：
2018-04-06
影响因子：
14.9
通讯作者：
Takata M
中科院分区：
文献类型：
--
作者：
Okamoto Y;Iwasaki WM;Kugou K;Takahashi KK;Oda A;Sato K;Kobayashi W;Kawai H;Sakasai R;Takaori-Kondo A;Yamamoto T;Kanemaki MT;Taoka M;Isobe T;Kurumizaka H;Innan H;Ohta K;Ishiai M;Takata M
在低剂量阿非迪霉素（APH）处理引起的轻度复制应激期间，关键的范可尼贫血蛋白FANCD 2在常见的脆性位点上积累，观察为姐妹灶，并保护基因组稳定性。为了进一步了解FANCD 2的功能及其调控机制，我们通过ChIP-seq分析研究了FANCD 2在这种情况下的全基因组染色质定位。我们发现FANCD 2主要聚集在一组与已知CFS广泛重叠的大转录基因的中心区域。与以前的研究一致，我们发现这种FANCD 2保留是R环依赖性的。然而，FANCD 2单泛素化和RPA灶形成仍然在R环耗尽的细胞中诱导。有趣的是，我们检测到APH处理后FANCD 2和R环之间的近端连接测定点增加，这被转录抑制所抑制。总的来说，我们的数据表明，R-环需要保留FANCD 2在染色质中的大基因的中间内含子区域，而复制应激诱导的上游事件导致FA途径激活不是由R-环触发。
During mild replication stress provoked by low dose aphidicolin (APH) treatment, the key Fanconi anemia protein FANCD2 accumulates on common fragile sites, observed as sister foci, and protects genome stability. To gain further insights into FANCD2 function and its regulatory mechanisms, we examined the genome-wide chromatin localization of FANCD2 in this setting by ChIP-seq analysis. We found that FANCD2 mostly accumulates in the central regions of a set of large transcribed genes that were extensively overlapped with known CFS. Consistent with previous studies, we found that this FANCD2 retention is R-loop-dependent. However, FANCD2 monoubiquitination and RPA foci formation were still induced in cells depleted of R-loops. Interestingly, we detected increased Proximal Ligation Assay dots between FANCD2 and R-loops following APH treatment, which was suppressed by transcriptional inhibition. Collectively, our data suggested that R-loops are required to retain FANCD2 in chromatin at the middle intronic region of large genes, while the replication stress-induced upstream events leading to the FA pathway activation are not triggered by R-loops.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
DOI：
10.1038/nrc.2017.52
发表时间：
2017-07-25
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Glover TW;Wilson TE;Arlt MF
通讯作者：
Arlt MF
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.