Polλ promotes microhomology-mediated end-joining.
Polλ promotes microhomology-mediated end-joining.
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DOI：
10.1038/s41594-022-00895-4
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发表时间：
2023-01
影响因子：
16.8
通讯作者：
Pomerantz, Richard T.
中科院分区：
文献类型：
--
作者：
Chandramouly, Gurushankar;Jamsen, Joonas;Borisonnik, Nikita;Tyagi, Mrityunjay;Calbert, Marissa L.;Tredinnick, Taylor;Ozdemir, Ahmet Y.;Kent, Tatiana;Demidova, Elena V.;Arora, Sanjeevani;Wilson, Samuel H.;Pomerantz, Richard T.
被称为微同源介导的末端连接（MMEJ）的双链断裂（DSB）修复途径被认为依赖于DNA聚合酶θ（Polθ）并且独立于非同源末端连接（NHEJ）因子而发生。一个尚未解决的问题是MMEJ是否是由一个单一的Polθ介导的末端连接途径或由其他未发现的途径。我们发现，在NHEJ中发挥作用的人类X家族Polλ还表现出与Polθ一样的强大MMEJ活性。Polλ在哺乳动物细胞中独立于必需的NHEJ因子LIG 4/XRCC 4和Polθ促进MMEJ，这揭示了独特的Polλ依赖性MMEJ机制。采用原位光诱导DSB形成的X射线晶体学捕获了Polλ在稳定微同源介导的DNA突触的行为中与2.0 μ m分辨率的传入核苷酸，并揭示了Polλ如何通过最小碱基配对连接的DNA突触进行复制。最后，我们发现Polλ与BRCA 1和BRCA 2是半合成致死的。总之，这些研究表明Polλ MMEJ是一种独特的DSB修复机制。
The double-strand break (DSB) repair pathway called microhomology-mediated end-joining (MMEJ) is thought to be dependent on DNA polymerase theta (Polθ) and occur independently of nonhomologous end-joining (NHEJ) factors. An unresolved question is whether MMEJ is facilitated by a single Polθ-mediated end-joining pathway or consists of additional undiscovered pathways. We find that human X-family Polλ, which functions in NHEJ, additionally exhibits robust MMEJ activity like Polθ. Polλ promotes MMEJ in mammalian cells independently of essential NHEJ factors LIG4/XRCC4 and Polθ, which reveals a distinct Polλ-dependent MMEJ mechanism. X-ray crystallography employing in situ photo-induced DSB formation captured Polλ in the act of stabilizing a microhomology-mediated DNA synapse with incoming nucleotide at 2.0 Å resolution and reveals how Polλ performs replication across a DNA synapse joined by minimal base-pairing. Last, we find that Polλ is semisynthetic lethal with BRCA1 and BRCA2. Together, these studies indicate Polλ MMEJ as a distinct DSB repair mechanism.
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影响因子：
8.8
作者：
Chandramouly G;Liao S;Rusanov T;Borisonnik N;Calbert ML;Kent T;Sullivan-Reed K;Vekariya U;Kashkina E;Skorski T;Yan H;Pomerantz RT
通讯作者：
Pomerantz RT
影响因子：
14.9
作者：
Crespan, Emmanuele;Czabany, Tibor;Huebscher, Ulrich
通讯作者：
Huebscher, Ulrich
影响因子：
3.7
作者：
Braithwaite EK;Kedar PS;Stumpo DJ;Bertocci B;Freedman JH;Samson LD;Wilson SH
通讯作者：
Wilson SH
影响因子：
2.8
作者：
Beardslee, Renee A.;Suarez, Samuel C.;Toffton, Shannon M.;McCulloch, Scott D.
通讯作者：
McCulloch, Scott D.
DOI：
10.1073/pnas.0915067107
发表时间：
2010-02-16
影响因子：
11.1
作者：
Boboila, Cristian;Jankovic, Mila;Alt, Frederick W.
通讯作者：
Alt, Frederick W.