Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells.
Mitotic DNA synthesis is caused by transcription-replication conflicts in BRCA2-deficient cells.
复制标题
DOI：
10.1016/j.molcel.2022.07.011
复制
发表时间：
2022-09-15
期刊：
影响因子：
16
通讯作者：
Tarsounas, Madalena
中科院分区：
文献类型：
--
作者：
Groelly, Florian J.;Dagg, Rebecca A.;Petropoulos, Michalis;Rossetti, Giacomo G.;Prasad, Birbal;Panagopoulos, Andreas;Paulsen, Teressa;Karamichali, Angeliki;Jones, Samuel E.;Ochs, Fena;Dionellis, Vasilis S.;Lombardi, Emilia Puig;Miossec, Matthieu J.;Lockstone, Helen;Legube, Gaelle;Blackford, Andrew N.;Altmeyer, Matthias;Halazonetis, Thanos D.;Tarsounas, Madalena
异常复制导致缺乏BRCA 2的细胞进入复制不足的DNA的有丝分裂，这激活了被称为有丝分裂DNA合成（MiDAS）的修复机制。在这里，我们确定了全基因组的位点，当BRCA 2被废除时，MiDAS反应发生。高分辨率分析显示，这些网站是不同的MiDAS在aphidicolin诱导的常见的脆性位点，因为它们映射到基因组区域复制在早期S期，这是接近早期点火复制起点，高度转录，并显示R环形成的潜力。早期S期的转录抑制和RNaseH 1过表达都减少了BRCA 2缺陷细胞中的MiDAS，表明转录-复制冲突（TRC）和R环是MiDAS的来源。重要的是，在BRCA 2缺陷细胞中鉴定的MiDAS位点也代表了BRCA 2突变乳腺肿瘤中基因组重排的热点。因此，我们的工作提供了一种机制，说明肿瘤易感BRCA 2失活如何将转录诱导的DNA损伤与有丝分裂DNA修复联系起来，以促进癌细胞的基因组不稳定性特征。BRCA 2缺失在早期S期复制的位点触发有丝分裂DNA合成（MiDAS）转录-复制冲突和R环是MiDAS激活的基础由BRCA 2缺失触发的MiDAS位点与由蚜虫菌素引起的位点不同RAD 52介导的MiDAS促进BRCA 2缺陷细胞中的基因组完整性BRCA 2缺陷细胞激活有丝分裂DNA合成（MiDAS）以完成基因组复制。Groelly等人表明在缺乏BRCA 2的情况下，MiDAS起源于由早期S期的转录-复制冲突（TRC）和R环引起的DNA损伤。因此，这些网站是不同的aphidicolin诱导常见的脆性网站。
Aberrant replication causes cells lacking BRCA2 to enter mitosis with under-replicated DNA, which activates a repair mechanism known as mitotic DNA synthesis (MiDAS). Here, we identify genome-wide the sites where MiDAS reactions occur when BRCA2 is abrogated. High-resolution profiling revealed that these sites are different from MiDAS at aphidicolin-induced common fragile sites in that they map to genomic regions replicating in the early S-phase, which are close to early-firing replication origins, are highly transcribed, and display R-loop-forming potential. Both transcription inhibition in early S-phase and RNaseH1 overexpression reduced MiDAS in BRCA2-deficient cells, indicating that transcription-replication conflicts (TRCs) and R-loops are the source of MiDAS. Importantly, the MiDAS sites identified in BRCA2-deficient cells also represent hotspots for genomic rearrangements in BRCA2-mutated breast tumors. Thus, our work provides a mechanism for how tumor-predisposing BRCA2 inactivation links transcription-induced DNA damage with mitotic DNA repair to fuel the genomic instability characteristic of cancer cells. BRCA2 loss triggers mitotic DNA synthesis (MiDAS) at loci that replicate in early S-phase Transcription-replication conflicts and R-loops underlie MiDAS activation MiDAS sites triggered by BRCA2 loss are distinct from those caused by aphidicolin RAD52-mediated MiDAS promotes genome integrity in BRCA2-deficient cells BRCA2-deficient cells activate mitotic DNA synthesis (MiDAS) to complete genome duplication. Groelly et al. show that in the absence of BRCA2, MiDAS originates from DNA lesions caused by transcription-replication conflicts (TRCs) and R-loops during the early S-phase. These sites are therefore distinct from aphidicolin-induced common fragile sites.
登录
查看更多内容
DOI：
10.1083/jcb.202101092
发表时间：
2021-09-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Crossley MP;Brickner JR;Song C;Zar SMT;Maw SS;Chédin F;Tsai MS;Cimprich KA
通讯作者：
Cimprich KA
影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
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：
16
作者：
Chappidi, Nagaraja;Nascakova, Zuzana;Janscak, Pavel
通讯作者：
Janscak, Pavel