Repriming of DNA synthesis at stalled replication forks by human Prim Pol
Repriming of DNA synthesis at stalled replication forks by human Prim Pol
复制标题
DOI：
10.1038/nsmb.2719
复制
发表时间：
2013-12-01
影响因子：
16.8
通讯作者：
Mendez, Juan
中科院分区：
文献类型：
--
作者：
Mouron, Silvana;Rodriguez-Acebes, Sara;Mendez, Juan
DNA复制叉在基因组复制过程中崩溃，导致双链断裂，对基因组稳定性构成威胁。在复制抑制剂存在下或在紫外线照射后，叉塌陷的风险更高，这会在DNA结构中引入特定的修饰。在这些情况下，叉进展可能是由易错跨病变合成（TLS）DNA聚合酶促进。或者，复制体可以跳过受损的DNA，留下未复制的缺口在复制后修复。该机制严格要求在病变下游发生预充事件。在这里，我们表明，PrimPol，一种新的人类引发酶和TLS聚合酶，利用其引发酶活性介导紫外线照射后不间断的叉进展和dNTP耗尽后重新启动DNA合成。作为一种参与DNA损伤耐受的酶，PrimPol可能成为癌症治疗的靶点。
DNA replication forks that collapse during the process of genomic duplication lead to double-strand breaks and constitute a threat to genomic stability. The risk of fork collapse is higher in the presence of replication inhibitors or after UV irradiation, which introduces specific modifications in the structure of DNA. In these cases, fork progression may be facilitated by errorprone translesion synthesis (TLS) DNA polymerases. Alternatively, the replisome may skip the damaged DNA, leaving an unreplicated gap to be repaired after replication. This mechanism strictly requires a priming event downstream of the lesion. Here we show that PrimPol, a new human primase and TLS polymerase, uses its primase activity to mediate uninterrupted fork progression after UV irradiation and to reinitiate DNA synthesis after dNTP depletion. As an enzyme involved in tolerance to DNA damage, PrimPol might become a target for cancer therapy.