PARP1對於PRR機制 (Post-replication repair)中反向複製叉的形成有著重要的作用，反向複製叉可以在DNA損傷發生後停止並保護DNA複製叉，防止DNA損傷進一步擴大，但是目前PARP1是如何參與PRR機制並調控反向複製叉的生成還有待研究。在本篇研究中我們通過CRISPR技術產生了PARP1 knockout細胞株，我們發現與野生型細胞相比PARP1 knockout細胞株在面對HU (Hydroxyurea)所造成的複製壓力時，DNA的複製速率會有增加的趨勢，而在面對MMS (Methyl methane sulfonate)產生的複製壓力時，PARP1 knockout細胞株的複製速率又會低於野生型細胞。我們的研究成果顯示PARP1缺乏細胞複製速率的增減，取決於複製壓力的類型。另外PARP1的抑制或缺乏會導致homologous recombination defective cells (例如BRCA1/2突變細胞)產生加成性致死 (Synthetic lethal)。利用此機制目前臨床上開發出PARP1抑制劑Olaparib，用於治療BRCA1/2突變的癌症，但是抗藥性問題使得Olaparib的泛用性大大的降低，我們與成功大學化學系的邱顯泰教授合作，嘗試尋找可以治療BRCA2突變癌細胞的藥物，利用結腸癌細胞HCT116 及HCT116 BRCA2-/-測試從邱老師實驗室所合成的30種化合物。最後通過兩輪篩選我們發現2種化合物對於BRCA2-/-細胞似乎具有加成性致死的的效果，但都不比Olaparib有效。HCT116細胞株是良好的藥物篩選平台，可以篩選更多化合物期待能找到與Olaparib一樣甚至具有更好效果的藥物。

PARP1 plays an important role in the formation of reverse forks in response to replication stress. The formation of reversed forks protects stalling forks from collapse into DNA double-strand breaks and are vital to maintain genome stability. However, it remains unclear how PARP1 participates in the formation of reversed forks. Here, we generated the PARP1-knockout human cell lines by using CRISPR-mediated gene knockout strategy. We found that the depletion of PARP1 results in longer replication tracks in response to hydroxyurea (HU)-induced replication stress compared with wild type cells. By contrast, the depletion of PARP1 further reduces the length of replication tracks in response to methyl methane sulfonate (MMS)-induced replication stress. Our results indicate that the progression of replication tracks during replication stress depends on types of DNA lesions. Additionally, the inhibition of PARP1 shows synthetic lethal phenotypes in the homologous recombination (HR)-defective cells, such as BRCA1 or BRCA2 mutant cells. Therefore, the PARP1 inhibitors, such as Olaparib, has been developed to treat the BRCA1 or BRCA2 mutant cancers successfully. However, drug resistance occurs and has become an obstacle for the efficacy of the treatment. In order to develop new chemicals to treat HR-defective mutant cancers, we perform drug screening from chemical deposits kindly provided by Dr. Hsien-Tai Chiu, Dept of Chemistry, National Cheng Kung University. We used the BRCA2-deficient colorectal cell line HCT116 (BRCA2-/-) to screen for chemicals. In the end, we found two chemicals that show more sensitive in BRCA2-/- cells than the wild type cells. However, comparing with Olaparib, the two chemicals are not as effective as Olaparib. The BRCA2-/- cells are good platform to screen for chemicals. Further screening can be conducted to find chemicals that are as effective as Olaparib.

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