DNA repair protein RAD52 is required for protecting G-quadruplexes in mammalian cells.
DNA repair protein RAD52 is required for protecting G-quadruplexes in mammalian cells.
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DOI：
10.1016/j.jbc.2022.102770
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Wu, Xiaohua
中科院分区：
文献类型：
--
作者：
Liu, Shuo;Wang, Zi;Shah, Sameer Bikram;Chang, Chia-Yu;Ai, Michael;Nguyen, Tran;Xiang, Rong;Wu, Xiaohua
G-四链体（G4）形成DNA序列在人类基因组中大量存在，是引起DNA双链断裂和基因组不稳定的热点。保护G4和维持基因组稳定性的机制尚未完全阐明。在这里，我们证明了RAD 52在抑制G4期DSB积累中起重要作用，并且RAD 52缺陷细胞对G4稳定化合物敏感。从机制上讲，我们表明，RAD 52是在G4有效的同源重组修复所必需的，这可能是由于其在招募结构特异性核酸内切酶XPF以去除DSB末端的G4结构中的功能。我们还证明了在G4稳定化后，内切核酸酶MUS 81介导G4处停滞的复制叉的切割。所得的DSB将RAD 52和XPF募集到G4用于加工DSB末端以促进同源重组修复。RAD 52沿着与G4-分解解旋酶FANCJ的损失导致在用G4-稳定化合物吡多他汀处理之前和之后DSB积累的显著增加，并且RAD 52表现出与FANCJ的合成致死相互作用。总的来说，我们的研究结果揭示了RAD 52在保护G4完整性方面的新作用，并为新的癌症治疗策略提供了见解。
G-quadruplex (G4)-forming DNA sequences are abundant in the human genome, and they are hot spots for inducing DNA double-strand breaks (DSBs) and genome instability. The mechanisms involved in protecting G4s and maintaining genome stability have not been fully elucidated. Here, we demonstrated that RAD52 plays an important role in suppressing DSB accumulation at G4s, and RAD52-deficient cells are sensitive to G4-stabilizing compounds. Mechanistically, we showed that RAD52 is required for efficient homologous recombination repair at G4s, likely due to its function in recruiting structure-specific endonuclease XPF to remove G4 structures at DSB ends. We also demonstrated that upon G4 stabilization, endonuclease MUS81 mediates cleavage of stalled replication forks at G4s. The resulting DSBs recruit RAD52 and XPF to G4s for processing DSB ends to facilitate homologous recombination repair. Loss of RAD52 along with G4-resolving helicase FANCJ leads to a significant increase of DSB accumulation before and after treatment with the G4-stabilizing compound pyridostatin, and RAD52 exhibits a synthetic lethal interaction with FANCJ. Collectively, our findings reveal a new role of RAD52 in protecting G4 integrity and provide insights for new cancer treatment strategies.
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影响因子：
46.9
作者：
Chambers, Vicki S.;Marsico, Giovanni;Balasubramanian, Shankar
通讯作者：
Balasubramanian, Shankar
DOI：
10.15252/embj.201488663
发表时间：
2014-11-03
期刊：
The EMBO journal
影响因子：
--
作者：
Castillo Bosch P;Segura-Bayona S;Koole W;van Heteren JT;Dewar JM;Tijsterman M;Knipscheer P
通讯作者：
Knipscheer P
影响因子：
3.7
作者：
Brosh RM Jr;Cantor SB
通讯作者：
Cantor SB
影响因子：
16
作者：
Davies, AA;Masson, JY;West, SC
通讯作者：
West, SC
影响因子：
37.3
作者：
Kosiol N;Juranek S;Brossart P;Heine A;Paeschke K
通讯作者：
Paeschke K