Replication protein A associates with nucleolar R loops and regulates rRNA transcription and nucleolar morphology.
Replication protein A associates with nucleolar R loops and regulates rRNA transcription and nucleolar morphology.
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DOI：
10.1101/gad.348858.121
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发表时间：
2021-12-01
影响因子：
10.5
通讯作者：
Manley JL
中科院分区：
文献类型：
--
作者：
Feng S;Manley JL
在这里，Feng和Manley报道了DNA复制和修复因子复制蛋白A （RPA）在控制核仁稳态中的新功能。他们的发现既表明了RPA在核仁中通过pre-rRNA转录控制的新作用，也强调了RPA在核仁稳态中的功能在生理和病理条件下都与r环的分解有关。核核是一个重要的细胞区室，核糖体rna （rrna）在其中转录，对细胞生长至关重要的某些应激途径在这里协调。在这里，我们报道了DNA复制和修复因子复制蛋白A （RPA）在控制核仁稳态中的新功能。我们发现DNA:RNA解旋酶senataxin （SETX）的缺失促进了RPA核仁的定位，而这种再定位依赖于R环的存在。值得注意的是，这种核仁RPA表型在喜树碱（CPT）诱导的基因毒性应激和setx缺陷的AOA2患者成纤维细胞中也被观察到。扩展这些结果，我们发现RPA在CPT治疗后被招募到rDNA，其中RPA阻止r环诱导的DNA双链断裂。此外，我们发现RPA的缺失显著降低了47S pre-rRNA水平，同时RNAP ii介导的“启动子和pre-rRNA反义”RNA以及RNAP i转录的基因内间隔RNA的表达增加。最后，我们发现RPA的缺失促进了核仁结构的紊乱，其特征是核仁尺寸减小。我们的研究结果既表明RPA通过前rrna转录控制在核仁中发挥新的作用，也强调RPA在核仁稳态中的功能与生理和病理条件下的r环分解有关。
Here, Feng and Manley report novel functions of the DNA replication and repair factor replication protein A (RPA) in control of nucleolar homeostasis. Their findings both indicate new roles for RPA in nucleoli through pre-rRNA transcriptional control and also emphasize that RPA function in nucleolar homeostasis is linked to R-loop resolution under both physiological and pathological conditions. The nucleolus is an important cellular compartment in which ribosomal RNAs (rRNAs) are transcribed and where certain stress pathways that are crucial for cell growth are coordinated. Here we report novel functions of the DNA replication and repair factor replication protein A (RPA) in control of nucleolar homeostasis. We show that loss of the DNA:RNA helicase senataxin (SETX) promotes RPA nucleolar localization, and that this relocalization is dependent on the presence of R loops. Notably, this nucleolar RPA phenotype was also observed in the presence of camptothecin (CPT)-induced genotoxic stress, as well as in SETX-deficient AOA2 patient fibroblasts. Extending these results, we found that RPA is recruited to rDNA following CPT treatment, where RPA prevents R-loop-induced DNA double-strand breaks. Furthermore, we show that loss of RPA significantly decreased 47S pre-rRNA levels, which was accompanied by increased expression of both RNAP II-mediated “promoter and pre-rRNA antisense” RNA as well as RNAP I-transcribed intragenic spacer RNAs. Finally, and likely reflecting the above, we found that loss of RPA promoted nucleolar structural disorganization, characterized by the appearance of reduced size nucleoli. Our findings both indicate new roles for RPA in nucleoli through pre-rRNA transcriptional control and also emphasize that RPA function in nucleolar homeostasis is linked to R-loop resolution under both physiological and pathological conditions.
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影响因子：
8.8
作者：
Harding SM;Boiarsky JA;Greenberg RA
通讯作者：
Greenberg RA
影响因子：
5.4
作者：
Grummt, Ingrid
通讯作者：
Grummt, Ingrid
影响因子：
4.8
作者：
Christensen, MO;Krokowski, RM;Mielke, C
通讯作者：
Mielke, C
影响因子：
16
作者：
Hatchi, Elodie;Skourti-Stathaki, Konstantina;Ventz, Steffen;Pinello, Luca;Yen, Angela;Kamieniarz-Gdula, Kinga;Dimitrov, Stoil;Pathania, Shailja;McKinney, Kristine M.;Eaton, Matthew L.;Kellis, Manolis;Hill, Sarah J.;Parmigiani, Giovanni;Proudfoot, Nicholas J.;Livingston, David M.
通讯作者：
Livingston, David M.
抑制RNA聚合酶I作为促进p53癌症特异性激活的治疗策略。
影响因子：
50.3
作者：
Bywater MJ;Poortinga G;Sanij E;Hein N;Peck A;Cullinane C;Wall M;Cluse L;Drygin D;Anderes K;Huser N;Proffitt C;Bliesath J;Haddach M;Schwaebe MK;Ryckman DM;Rice WG;Schmitt C;Lowe SW;Johnstone RW;Pearson RB;McArthur GA;Hannan RD
通讯作者：
Hannan RD