DNA 損傷耐受機制(DNA damage tolerance, DDT)也稱之為複製後修飾機制(Post-replication repair, PRR)，對於保持基因體的完整相當重要。 缺乏DDT可導致DNA複製叉停滯和雙股DNA斷裂（Double strand break, DSB）的數量增加，最終使基因體不穩定性。模板轉換（Template-switch, TS）是DDT其中一個分支，PCNA受E2泛素酶UBC13、MMS2和E3泛素連接酶HLTF、SHPRH產生賴氨酸63所連接的聚泛素化調節。然而TS的詳細機制仍不清楚。先前我們利用免疫共沉澱實驗鑑定出HLTF與PARP1有相互作用。在本次研究中，我們進一步確定HLTF不僅與PARP1相互作用也能與BARD1相互作用。HLTF利用HIRAN和DEXDc區域與PARP1行交互作用並利用HIRAN區域與BARD1行交互作用。當下調PARP1的表現量後，標定的新合成DNA明顯不能繞過MMS所產生的DNA障礙而變短，同時有較多標定的DNA卡損在復制叉中無法繼續複製，缺乏繞過DNA障礙的能力在利用CRISPR-Cas9系統所生產的完全缺失PARP1細胞株也得到相似結果，完全缺失PARP1造成大量姊妹染色體互換(sister chromatid exchanges SCE)，表示其在複製叉中產生大量DSB。完全缺失PARP1在面臨順鉑或MMS時有非常顯著的藥物敏感性。最後我們發現當細胞中過度表現PARP1的DNA結合結構區域（PARP1-DBD）時，細胞複製叉會形成大量的SCE，此細胞增加DSB的現象和完全缺失PARP1細胞株相當類似，表示PARP1-DBD可影響內生性PARP1的正常功能。最終我們的結果證明PARP1可調控TS機制。當PARP1缺失時會導致TS機制受損，進而增加複製叉停滯以及DSB的數量。

The DNA damage tolerance (DDT) pathway, also known as post-replication repair (PRR), plays an important role in the maintenance of genome integrity. Defects in the DDT pathway can cause increasing numbers of stalled DNA replication forks and DNA double strand breaks (DSB), and as a result, can cause genomic instability. One branch of DDT, known as template switching (TS) is regulated by the lysine 63-linked polyubiquitination of PCNA generated by the ubiquitin E2 enzymes UBC13 and MMS2, and the ubiquitin E3 ligases HLTF and SHPRH. However, the detailed mechanism by which this occurs remains unclear. Previously, using a coimmunoprecipitation assay, we found that HLTF interacts with PARP1. In this study, we further identified that HLTF not only interacts with PARP1, but also interacts with BARD1. We revealed that HLTF utilizes HIRAN and the DEXDc domain to interact with PARP1 and utilizes the HIRAN domain to interact with BARD1. Additionally, a DNA fiber assay indicated that the depletion of PARP1 reduces the replication track length in response to methyl methanesulfonate (MMS)-induced DNA lesions and simultaneously increases the number of stalled forks. Similar results were also shown in the PARP1 null mutant, which is generated by the CRISPR-Cas9 system. Significantly, the PARP1 null mutant exhibits elevated sister chromatid exchanges (SCEs), indicating that an increased number of DSB is generated in the mutant cells. The PARP1 null mutant is sensitive to DNA damaging agents such as MMS and cisplatin. Furthermore, overexpression of the DNA binding domain of PARP1 (PARP1-DBD) can significantly increases SCEs, a phenotype similar to the PARP1 null mutant, indicating that PARP1-DBD can interfere with the function of endogenous PARP1. Taken together, our results suggest that PARP1 is involved in the TS pathway. The depletion of PARP1 can result in defective TS, and as a result can cause an increasing number of stalled forks and DSBs.

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