SAMHD1 restrains aberrant nucleotide insertions at repair junctions generated by DNA end joining.
SAMHD1 restrains aberrant nucleotide insertions at repair junctions generated by DNA end joining.
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DOI：
10.1093/nar/gkab051
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发表时间：
2021-03-18
影响因子：
14.9
通讯作者：
Geisberger R
中科院分区：
文献类型：
--
作者：
Akimova E;Gassner FJ;Schubert M;Rebhandl S;Arzt C;Rauscher S;Tober V;Zaborsky N;Greil R;Geisberger R
DNA双链断裂的异常末端连接导致染色体重排和核或线粒体DNA插入断裂点，这在癌细胞中常见，并构成对基因组完整性的主要威胁。然而，导致这些插入的机制在很大程度上是未知的。通过监测不同线形DNA底物在HEK293细胞中的末端连接，以及通过检测CRISPR/Cas9在HEK293和HeLa细胞中诱导的DNA断裂的末端连接，我们提供了SAMHD1的dNTPase活性阻止DNA末端连接过程中DNA断裂处异常DNA再合成的证据。因此，SAMHD1表达或细胞内dNTP水平低会导致修复关节较短，并阻碍末端修复之前远处DNA区域的插入。我们的结果揭示了SAMHD1在DNA末端连接中的一个新角色，并为SAMHD1缺失如何导致基因组不稳定和癌症发展提供了新的见解。DNTPase SAMHD1将dNTP水平保持在中等水平，与异常的悬垂再合成和DNA修复关节处的插入不相容。
Aberrant end joining of DNA double strand breaks leads to chromosomal rearrangements and to insertion of nuclear or mitochondrial DNA into breakpoints, which is commonly observed in cancer cells and constitutes a major threat to genome integrity. However, the mechanisms that are causative for these insertions are largely unknown. By monitoring end joining of different linear DNA substrates introduced into HEK293 cells, as well as by examining end joining of CRISPR/Cas9 induced DNA breaks in HEK293 and HeLa cells, we provide evidence that the dNTPase activity of SAMHD1 impedes aberrant DNA resynthesis at DNA breaks during DNA end joining. Hence, SAMHD1 expression or low intracellular dNTP levels lead to shorter repair joints and impede insertion of distant DNA regions prior end repair. Our results reveal a novel role for SAMHD1 in DNA end joining and provide new insights into how loss of SAMHD1 may contribute to genome instability and cancer development. The dNTPase SAMHD1 keeps dNTP levels at moderate levels, incompatible with aberrant overhang resynthesis and insertions at DNA repair joints.
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影响因子：
82.9
作者：
通讯作者：
--
影响因子：
48
作者：
Crosetto, Nicola;Mitra, Abhishek;Silva, Maria Joao;Bienko, Magda;Dojer, Norbert;Wang, Qi;Karaca, Elif;Chiarle, Roberto;Skrzypczak, Magdalena;Ginalski, Krzysztof;Pasero, Philippe;Rowicka, Maga;Dikic, Ivan
通讯作者：
Dikic, Ivan
影响因子：
64.8
作者：
Goldstone, David C.;Ennis-Adeniran, Valerie;Webb, Michelle
通讯作者：
Webb, Michelle
DOI：
10.1073/pnas.1321889111
发表时间：
2014-05-27
影响因子：
11.1
作者：
Onozawa, Masahiro;Zhang, Zhenhua;Aplan, Peter D.
通讯作者：
Aplan, Peter D.
影响因子：
3.5
作者：
Pai CC;Kearsey SE
通讯作者：
Kearsey SE