現今利用順鉑進行慢性治療在癌症細胞中產生化學抗性，這已成為癌症治療上主要的障礙。順鉑引起鹼基之間的股間交連作用（interstrand cross-links, ICLs）。在哺乳動物細胞中，主要是由范可尼貧血修復路徑（Faconi anemia, FA）以及同源重組修復路徑（Homologous recombination, HR）修補ICLs。MOZ屬於MYST家族組蛋白乙醯轉移酶其中一員，參與特定基因轉錄調控、DNA修復以及複製。在這項研究中，我們發現MOZ在具有順鉑抗藥性的鼻咽癌細胞株（chemoresistant nasopharyngeal carcinoma cells, NPC）HONE6細胞與其親代HONE1細胞相比有過度表現的情況。此外，我們利用 CRISPR-Cas9降低HONE6細胞中MOZ表現量，進而產生了MOZ haploinsufficient細胞株。本篇研究發現，在MOZ haploinsufficient細胞中，參與在HR以及FA修復路徑中關鍵蛋白BRCA1、BRCA2以及FANCD2的表現量有降低的趨勢，並降低姊妹染色單體交換（Sister chromatid exchange, SCE）的頻率。細胞利用HR進行DNA斷裂末端修復進而產生SCE，在 MOZ haploinsufficient細胞中SCE的交換頻率大幅降低，這支持MOZ促進FA以及HR修復路徑的觀點。此外，複製後修復（Post-replication repair, PRR）中的模板交換路徑（Template switching, TS），在沒有DNA損傷處理下例如：甲磺酸甲酯（methyl methamesulfonate, MMS），MOZ haploinsufficient細胞中，stalled forks的數量增加以及複製軌道的長度有縮短的趨勢，此結果顯示MOZ參與並影響複製叉的進展。反之，在MMS存在的情況下，MOZ haploinsufficient細胞中，stalled forks的數量的大幅增加以及複製軌道的長度大幅縮短的趨勢。UBC13主要參與PRR修復路徑中的TS路徑，研究發現，MOZ會調節UBC13表現量，由此結果可知MOZ會參與在TS路徑。為了證明此結果，我們利用iPOND分析MOZ與複製叉的關聯性。在MMS處理的情況下，MOZ以及H3ac在stalled forks上有累積的情況。總結以上結果推測，MOZ不僅參與FA以及HR路徑，也參與TS路徑。MOZ的過度表現並調控參與FA、HR以及TS路經中蛋白的表現量進而造成抗藥性。

Chronic treatment with cisplatin can cause a chemoresistant phenotype of cancer cells, which has become a major obstacle to treatment efficacy. Cisplatin causes the interstrand cross-links (ICLs) between bases. The Fanconi anemia (FA) pathway combined with the homologous recombination (HR) pathway is the major pathway for the repair of these ICLs in mammalian cells. MOZ belongs to the MYST family of histone acetytranferases and is involved in gene specific transcription regulation, DNA repair, and replication. In this study, we found that MOZ is overexpressed in the chemoresistant nasopharyngeal carcinoma cells (NPC), HONE6 cells, as compared to its parental HONE1 cells. Additionally, we have generated the MOZ haploinsufficient HONE6 cells by using the CRISPR-Cas9 gene deletion strategy. Here, we showed that the MOZ haploinsufficient cells reduced the expression of BRCA1, BRCA2, and FANCD2, which are involved in the HR and FA pathways, and reduced the frequency of sister chromatid exchanges (SCEs). Because SCE is the result of repairing DNA broken ends by the HR pathway, the reduced SCE in the MOZ haploinsufficient HONE6 cells support the notion that MOZ facilitates the FA and HR pathways. Furthermore, in the templating switching (TS) pathway of the post-replication repair (PRR) pathway, the MOZ haploinsufficient cells showed reduced replication tracks, concomitantly with an increased number of stalled forks in the absence of DNA damaging treatment, e.g. methyl methamesulfonate (MMS), indicating that MOZ is involved in the progression of replication forks. In the presence of MMS, the track length is further reduced, and the number of stalled forks is further increased in the MOZ haploinsufficient cells. Since MOZ also regulates the expression of UBC13, involved in the TS pathway of the PRR pathway, our results suggest that MOZ participates in the TS pathway. In support of this notion, MOZ is associated with replication forks by using the iPOND assay. In the presence of MMS, MOZ and H3ac accumulated at a stalled fork. Taken together, our results suggest that MOZ is not only involved in the FA and HR pathways, but also participates in the TS pathway. Overexpression of MOZ could contribute to the chemoresistance by upregulation of the FA, HR and TS pathways.

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