C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.
C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption.
复制标题
DOI：
10.1038/s41467-023-40779-9
复制
发表时间：
2023-08-17
影响因子：
16.6
通讯作者：
Lakin, Nicholas D.
中科院分区：
文献类型：
--
作者：
Sharma, Abhishek Bharadwaj;Ramlee, Muhammad Khairul;Kosmin, Joel;Higgs, Martin R.;Wolstenholme, Amy;Ronson, George E.;Jones, Dylan;Ebner, Daniel;Shamkhi, Noor;Sims, David;Wijnhoven, Paul W. G.;Forment, Josep;Gibbs-Seymour, Ian;Lakin, Nicholas D.
虽然PARP抑制剂对同源重组（HR）缺陷细胞的毒性已得到充分证实，但与PARP 1/PARP 2破坏的其他合成致死相互作用尚不清楚。为了了解这些机制，我们对PARP 1/2基因破坏的合成致死基因进行了全基因组筛选，并将C16 orf 72/HAPSTR 1/TAPR 1鉴定为复制相关R环的新型调节剂。C16 orf 72在促进复制叉重新启动、抑制DNA损伤和维持基因组稳定性以响应复制应激方面至关重要。重要的是，C16 orf 72和PARP 1/2在平行途径中发挥作用，以抑制在停滞的复制叉处积累的DNA：RNA杂合体。从机制上讲，这是通过C16 orf 72与BRCA 1和RNA/DNA解旋酶Senataxin的相互作用来实现的，以促进它们募集到RNA：DNA杂合体中并赋予对PARP抑制剂的抗性。总之，这确定了C16 orf 72/Senataxin/BRCA 1依赖性途径，以抑制复制相关的R环积累，维持基因组稳定性并赋予对PARP抑制剂的抗性。在这里，作者确定C16 orf 72调节BRCA 1/Senataxin以促进复制叉恢复。这些蛋白在与PARP 1平行的途径中共同作用，以抑制响应复制应激的R环积累，并赋予对PARP抑制剂的抗性。
While the toxicity of PARP inhibitors to cells with defects in homologous recombination (HR) is well established, other synthetic lethal interactions with PARP1/PARP2 disruption are poorly defined. To inform on these mechanisms we conducted a genome-wide screen for genes that are synthetic lethal with PARP1/2 gene disruption and identified C16orf72/HAPSTR1/TAPR1 as a novel modulator of replication-associated R-loops. C16orf72 is critical to facilitate replication fork restart, suppress DNA damage and maintain genome stability in response to replication stress. Importantly, C16orf72 and PARP1/2 function in parallel pathways to suppress DNA:RNA hybrids that accumulate at stalled replication forks. Mechanistically, this is achieved through an interaction of C16orf72 with BRCA1 and the RNA/DNA helicase Senataxin to facilitate their recruitment to RNA:DNA hybrids and confer resistance to PARP inhibitors. Together, this identifies a C16orf72/Senataxin/BRCA1-dependent pathway to suppress replication-associated R-loop accumulation, maintain genome stability and confer resistance to PARP inhibitors. Here the authors identify that C16orf72 regulates BRCA1/Senataxin to promote replication fork recovery. These proteins act together in a pathway parallel to PARP1 to suppress R-loop accumulation in response to replication stress and confer resistance to PARP inhibitors.
登录
查看更多内容
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
DOI：
10.1073/pnas.2111262119
发表时间：
2022-07-05
影响因子：
11.1
作者：
通讯作者：
--
影响因子：
16
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
通讯作者：
Tarsounas, Madalena
影响因子：
16.8
作者：
Berti, Matteo;Chaudhuri, Arnab Ray;Thangavel, Saravanabhavan;Gomathinayagam, Shivasankari;Kenig, Sasa;Vujanovic, Marko;Odreman, Federico;Glatter, Timo;Graziano, Simona;Mendoza-Maldonado, Ramiro;Marino, Francesca;Lucic, Bojana;Biasin, Valentina;Gstaiger, Matthias;Aebersold, Ruedi;Sidorova, Julia M.;Monnat, Raymond J., Jr.;Lopes, Massimo;Vindigni, Alessandro
通讯作者：
Vindigni, Alessandro
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.