端粒縮短誘發回饋迴圈以增進末端保護

Telomere shortening Triggers a Feedback Loop to Enhance End Protection

楊家維(Chia-Wei Yang)

指導教授 ： 鄧述諄

國立臺灣大學/醫學院/微生物學研究所/博士(2017年)

https://doi.org/10.6342/NTU201701682

摘要

端粒的穩定由端粒酶與末端保護機制所調控。過短的端粒會活化DNA損傷感應激酶ATM/ATR並作用於端粒酶的聚集。然而，端粒的縮短是否也調控著末端保護機制仍然不甚清楚。在此，我揭示了一種反饋端保護的機制，此藉由酵母ATM/ATR控制著末端保護。Rap1的第731號絲氨酸處可被Tel1和Mec1激酶所磷酸化，而DNA損傷和端粒的縮短會促進該位點的磷酸化。Rap1磷酸化的缺失會降低Rap1與其相互作用的配偶體Rif1之間的相互作用，進而削弱了末端保護的強度。Rap1-Rif1結合的減少會損害端粒長度的調控並增加端粒與端粒間的重組機會。然而，受損的Rap1磷酸化既不影響端粒與端粒間的融合也不影響端粒沉默。這些結果顯示ATM/ATR的DNA損傷檢查點信號能藉由加強於短端粒上的Rap1-Rif1相互作用來控制端粒保護，檢查點激酶調節端粒酶的聚集與末端保護的途徑以維持端粒的穩定。

關鍵字

端粒 ； 保護 ； 端粒酶 ； Rap1 ； ATM/ATR

並列摘要

Telomere homeostasis is regulated by both telomerase and end protection mechanisms. Short telomere can activate DNA damage sensing kinases ATM/ATR for telomerase recruitment. However, it is still not clear whether telomere shortening also regulates end protection. Here I reveal a feedback end protection mechanism which regulated by yeast ATM/ATR under telomere stress. Rap1 is phosphorylated by Tel1 and Mec1 kinases at serine 731, and this phosphorylation is strengthened by DNA damage and telomere shortening. Loss of Rap1 phosphorylation decreases the interaction between Rap1 and its interacting partner Rif1, which further weakens the strength of end protection. Reduction of Rap1-Rif1 association impairs telomere length regulation and increases the change of telomere-telomere recombination. However, impaired Rap1 phosphorylation neither influences the telomere-telomere fusion nor the telomeric silencing. These results indicate that ATM/ATR DNA damage checkpoint signal controls the telomere protection by strengthening the Rap1-Rif1 interaction at short telomere, and the checkpoint kinase regulates both telomerase recruitment and end capping pathways to maintain telomere homeostasis.

並列關鍵字

Telomere ； capping ； telomerase ； Rap1 ； ATM/ATR

參考文獻

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