王廷方 Wang, Ting-Fang

分生所 研究員

減數分裂

減數分裂是孟德爾遺傳學的核心。減數分裂是真核生物有性生殖細胞專有的細胞分裂方式，它將雙倍體的生殖細胞染色體數目減半，製造出單倍體的精子、卵或真菌有性孢子。 我們以麵包酵母(Saccharomyces cerevisiae)、粟酒裂殖酵母(Schizosaccharomyces pombe)與工業用瑞氏木黴菌(Trichoderma reesei)為研究模式，利用遺傳學、分子生物學、生物化學、結構生物學、基因體學與生物資訊學等方法，探討減數分裂細胞中同源重組(homologous recombination; HR)、 DNA 損傷反應(DNA damage response)、聯會複合體(synaptonemal complex; SC)與DNA 甲基轉移酶 (methyltransferase)如何產生遺傳變異與維持基因體完整性。

聯會複合體 是由DNA與蛋白質組成拉鍊狀的複雜結構，其核心功能是穩定地將同源染色體連結起來，讓姐妹染色分體能精確配對，為遺傳重組提供骨架，確保減數分裂成功和增加後代變異性的關鍵。聯會複合體於1956年被發現，但其真實的生化功能仍未知。

我們最近的研究成果與方向可分為三大項：

參與麵包酵母菌減數分裂的HR蛋白質（Rad51、Rad54與Rad59）和組成SC的ZMM蛋白質(Zip1、Zip4、 Mer3與Msh4)均能抑制「DNA錯誤配對鹼基修復(Mismatch repair; MMR)」的活性，是「同種異族」生物雜交繁衍不可或缺的要件。我們利用全基因體研究數據與其它相關文獻資料，解釋過去30年來生物學與遺傳學教科書中關於「MMR導致相近物種雜交不孕與生殖隔離」舊理論的謬誤，再以「反向遺傳學(reverse genetics)」研究方法，找到12個專一性影響「同種異族雜交」酵母菌減數分裂的HR突變基因，相同的突變基因卻不影響「純品系」酵母菌減數分裂，證明多個HR蛋白質能抑制MMR活性，保留錯誤配對DNA鹼基。這個新發現的重要性之一是挑戰「HR是修補破損DNA最高保真度的機制」的舊學說。聯會複合體發現迄今近70年，但真正的生理功能仍未知。我們首次證明聯會複合體在減數分裂負責抑制MMR，促進DNA序列不完全相同的同源染色體進行重組互換，增加配子或真菌有性孢子的遺傳多樣性。

Figure 1

  1. *Ting-Fang Wang, and Ji-Long Liao (2026) Homologous recombination counteracts mismatch repair to promote fertility and genetic diversity. Trends in Genetics 42, 7-10. PMID: 41241584. (*corresponding author).
  2. #Ya-Ling Hung, #Chin-Ning Chuang, Hong-Xian Kim, Hou-Cheng Liu, Jhong-Syun Yao, Lavernchy Javanska, and *Ting-Fang Wang (2025) Rad51, Rad54, and ZMM proteins antagonize the mismatch repair system to promote fertility of budding yeast intraspecies hybrid zygotes. Nucleic Acids Research 53, gkaf847. PMID: 40902007 (#contributed equally).
  3. Ta-Ting Woo, Chi-Ning Chuang, Mika Higashide, Akira Shinohara, and *Ting-Fang Wang (2020) Dual roles of yeast Rad51 N-terminal domain in repairing DNA double-strand breaks. Nucleic Acids Research 48, 8474-8489 PMID:32652040.

 

大多數進行有性生殖的真核生物(如酵母菌、擔子菌、果蠅、線蟲、高等植物與哺乳類)的減數分裂細胞，都利用 Spo11 蛋白產生 DNA 雙股斷裂，從而啟動HR反應。我們發現剔除 spo11 基因的木黴菌仍能正常進行減數分裂與產生有新遺傳變異的有性孢子。 目前研究重點在探討木黴菌如何能在沒有Spo11啟動減數分裂HR反應。我們發現瑞氏木黴菌的DNA甲基轉移酶在減數分裂中具多項功能，第一是負責啟動減數分裂，第二是促進親代雙方同源染色體間HR反應，產生新遺傳變異。第三是以特殊表觀遺傳機制，將親代DNA上大量的胞嘧啶(cytosine) 甲基化，從而誘發點突變成胸腺嘧啶(thymine)，快速增加減數分裂產物（有性孢子）的基因體多樣性。遺傳變異過高的效應有如雙面刃，雖然有時能提升後代環境適應能力，但也常導致基因體產生不穩定性，造成有性孢子無法萌發成菌絲，又或者萌發出的新生菌絲無法正常進行營養生長。此新理論能解釋為何多數的野生木黴菌均為雌性或雄性不孕，僅憑藉菌絲營養生長而無性繁衍，因為更能維持基因體穩定性並延續既有生存優勢。

Figure 2

  1. #Lavernchy Jovanska, #I-Chen Lin, Jhong-Syuan Yao, Chia-Ling Chen, Hou-Cheng Liu, Wan-Chen Li, Yu-Chien Chuang, Albert Chen-Hsin Yu, Hisn-Nan Lin, Wen-Li Peng, Chang-I Yu, Ching-Yuan Su, Yi-Ping Chen, Ruey-Shyand Chen, Yi-Ping Hsueh, Hanna S Yuan, Ljudmilla Timofejeve, and *Ting-Fang Wang (2024) DNA cytosine methyltransferase differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei. Nucleic Acids Research 52, 9551-9537. PMID: 39021337.
  2. #Wan-Chen Li, #Chia-Yi Lee, #Wei-Hsuan Lan, #Tai-Ting Woo, Hou-Cheng Liu, Hsin-Yi Yen, Hao-Yen Chang, Yu-Chien Chuang, Chiung-Ya Chen, Chi-Ning Chuang, Chia-Ling Chen, Yi-Ping Hsueh, *Hung-Wen Li, *Peter Chi, and *Ting-Fang Wang (2021) Trichoderma reesei Rad51 tolerates mismatches in hybrid meiosis with diverse genome sequences. Proc. Natl. Acad. Sci. USA 118, e2007192118. PMID: 33593897.
  3. Hou-Cheng Liu, Wan-Chen Li, and *Ting-Fang Wang (2021) TSETA: a third-generation-sequencing based program for single-nucleotide-resolution mapping of meiotic recombination products and repeat-induced point mutations. Methods in Molecular Biology 2234, 331-361. PMID: 3316579.
  4. Wan-Chen Li, and *Ting-Fang Wang (2021) PacBio long-read sequencing, assembly, and Funannotate reannotation of the complete genome of Trichoderma reesei QM6a. Methods in Molecular Biology 2234, 311-329. PMID: 33165795.

 

真核生物在有絲分裂時進行一種「分離」的舞蹈。成對的姊妹染色分體，就像一對情侶，經過「濃縮」與「個別化」的過程，再由紡錘絲引領，分道揚鑣，成為兩個獨立的子細胞。動物和植物細胞在進行「開放式有絲分裂」時，核膜會先破裂，讓染色體得以分開，但如何防止細胞質與染色體混雜，依然是一個大謎團。胡曉棠博士利用了本院應用科學中心陳壁彰老師與王月廷開發的「胰蛋白酶與酪氨酰胺擴展顯微鏡」技術，成功解開了部分謎團。原來，Ki-67蛋白在細胞分裂時被磷酸化後，能夠控制核內脂質分子（如磷脂醯絲胺酸）聚集在染色體表面，形成了一種「染色體套膜」，有效防止了細胞質與染色體的混淆。這不僅是細胞生物學領域的一大突破，更對癌症腫瘤診斷具有重大助益。

Figure 3

  1. Hsiao-Tang Hu, Ueh-Ting Tim Wang, Bi-Chang Chen, *Yi-Ping Hsueh, and *Ting-Fang Wang (2025) Ki-67 and CDK1 control the dynamic association of nuclear lipids with mitotic chromosomes. Journal of Lipid Research 66, 100731. (This paper has been downloaded 1327 times since January, 2025, and was supported in part by an intramural grant (SPP) from IMB, Academia Sinica).

 

  • PDF, 1999-2000, Dept. Mol. & Cell Biol., Harvard Univ. USA
  • Ph.D., 1998, Dept. Mol. & Cell Biol., Harvard Univ. USA
  • MS, 1990, Inst. Life Science., Natl. Tsing Hua Univ.
  • BS, 1988, Dept. Chemistry, Natl. Taiwan Univ.
  1. Ting-Fang Wang# and Ji-Long Liao. (2025) Homologous recombination counteracts mismatch repair to promote fertility and genetic diversity. Trends in Genetics (PMID: 41241584; DOI: 10.1016/j.tig.2025.10.009)
  2. Ya-Ling Hung, Chi-Ning Chuang, Hong-Xiang Kim, Hou-Cheng Liu, Jhong-Syuan Yao, Lavernchy Jovanska, Yi-Ping Hsueh, Ruey-Shyang Chen, and Ting-Fang Wang# (2025) Rad51, Rad54, and ZMM proteins antagonize the mismatch repair system to promote fertility of budding yeast intraspecies hybrid zygotes. Nucleic Acids Research (PMID: 40902007; DOI: 10.1093/nar/gkaf847)
  3. Hsiao-Tang Hu, Ueh-Ting Tim Wang, Bi-Chang Chen, Yi-Ping Hsueh#, Ting-Fang Wang# (2025) Ki-67 and CDK1 control the dynamic association of nuclear lipids with mitotic chromosomes. Journal of Lipid Research ( PMID: 39706365; DOI: 10.1016/j.jlr.2024.100731)
  4. Lavernchy Jovanska, I-Chen Lin, Jhong-Syuan Yao, Chia-Ling Chen, Hou-Cheng Liu, Wan-Chen Li, Yu-Chien Chuang, Chi-Ning Chuang, Albert Chen-Hsin Yu, Hsin-Nan Lin, Wen-Li Pong, Chang-I Yu, Ching-Yuan Su, Yi-Ping Chen, Ruey-Shyang Chen, Yi-Ping Hsueh, Hanna S Yuan, Ljudmilla Timofejeva, Ting-Fang Wang# (2024) DNA cytosine methyltransferases differentially regulate genome-wide hypermutation and interhomolog recombination in Trichoderma reesei meiosis. Nucleic Acids Research (PMID: 39021337; DOI: 10.1093/nar/gkae611)
  5. Chi-Ning Chuang, Hou-Cheng Liu, Tai-Ting Woo, Ju-Lan Chao, Chiung-Ya Chen, Hisao-Tang Hu, Yi-Ping Hsueh, Ting-Fang Wang# (2024) Noncanonical usage of stop codons in ciliates expands proteins with structurally flexible Q-rich motifs. eLife (PMID: 38393970; DOI: 10.7554/eLife.91405)
  6. Chia-Lin Chen, Wan-Chen Li, Yu-Chien Chuang, Hou-Cheng Liu, Chien-Hao Huang, Ko-Yun Lo, Chung-Yu Chen, Fang-Mo Chang, Guo-An Chang, Yu-Ling Lin, Wen-denr Yang, Ching-Hua Su, Tsung-Ming Yeh, and Ting-Fang Wang# (2022) Sexual crossing, chromosome-level genome sequences, and comparative genomic analyses for the medicinal mushroom Taiwanofungus camphoratus (Syn. Antrodia cinnamomea; Antrodia camphorata). Microbiology spectrum (PMID: 35196809; DOI: 10.1128/spectrum.02032-21)
  7. Wan-Chen Li, Ting-Chan Lin, Chia-Ling Chen, Hou-Cheng Liu, Hisn-Nan Lin, Ju-Lan Chao, Cheng-Hsilin Hsieh, Hui-Fang Ni, Ruey-Shyang Chen# and Ting-Fang Wang# (2021) Complete genome sequences and genome-wide characterization of Trichoderma biocontrol agents provide new insights into their evolution and variation in genome organization, sexual development, and fungal-plant interactions. Microbiology spectrum (PMID: 34908505; DOI: 10.1128/Spectrum.00663-21)
  8. Wan-Chen Li, Chia-Yi Lee, Wei-Hsuan Lan, Tai-Ting Woo, Hou-Cheng Liu, Hsin-Yi Yeh, Hao-Yan Chang, Yu-Chien Chuang, Chi-Ning Chuang, Chia-Lin Chen, Yi-Ping Hsueh, Hung-Wen Li#, Peter Chi#, and Ting-Fang Wang# (2021) Trichoderma reesei Rad51 tolerates mismatches in hybrid meiosis with diverse genome sequences. Proceedings of the National Academy of Sciences (PMID: 33593897; DOI: 10.1073/pnas.2007192118)
  9. Wan-Chen Li and Ting-Fang Wang# (2021) PacBio long-read sequencing, assembly, and Funannotate reannotation of the complete genome of Trichoderma reesei QM6a. Methods in Molecular Biology (PMID: 33165795; DOI: 10.1007/978-1-0716-1048-0_21)
  10. Hou-Cheng Liu, Wan-Chen Li, and Ting-Fang Wang# (2021) TSETA: A third-generation sequencing-based computational tool for mapping and visualization of SNPs, meiotic recombination products, and RIP Mutations. Methods in Molecular Biology (PMID: 33165796; DOI: 10.1007/978-1-0716-1048-0_2)
  11. Tai-Ting Woo, Chi-Ning Chuang, Mika Higashide, Akira Shinohara, and Ting-Fang Wang# (2020) Dual roles of yeast Rad51 N-terminal domain in repairing DNA double-strand breaks. Nucleic Acids Research (PMID: 32652040; DOI: 10.1093/nar/gkaa587)
  12. Wan-Chen Li, Hou-Cheng Liu, Ying-Jyun Lin, Shu-Yun Tung, Ting-Fang Wang# (2020) Third-generation sequencing-based mapping and visualization of single nucleotide polymorphism, meiotic recombination, illegitimate mutation and repeat-induced point mutation. NAR Genomics and Bioinformatics (PMID: 33575607; DOI: 10.1093/nargab/lqaa056)
  • Wang, T.-F., Chin-Ning Chuang and Tai-Ting Woo. “Method and vector for enhancing protein expression”. US provisional application (63/036,704), Patent Cooperation Treaty application (PCT/US2021/036247) and Taiwan application (110120541).
  • Wang, T.-F., “Method for producing segmental aneuploidy (SAN) strains of Trichoderma reesei via sexual crossing and SAN strains produced therefrom”. Patent Cooperation Treaty (PCT/US14/58654) and US (9598738B2), Taiwan (I570236) and People’s Republic of China (IA001/ACA081CN).
  • Wang, T. F. and Yang, S.M. “Methods of producing virus-like particles of piconavirus using a small-ubiquitin-related fusion protein expression system”. US (8663951B2) and Taiwan (I415623).
  • Wang, T.-F. “SUMO fusion protein expression system for producing native proteins”. USA 8034910BZ.

主要研究員

王廷方 Ting-Fang Wang

博士研究生

洪雅玲 Ya-Ling Hung

博士後研究員

陳秋玲 Lavernchy Jovanska ． 廖吉隆 Ji-Long Liu

研究助理

莊齊寧 Chi-Ning Chuang ． 陳蘇杰 Su-Jie Chen ． 金紘翔 Hong-Xiang Kim ． 劉厚成 Hou-Cheng Liu ． 吳念琦 Nien-Chi Wu

Wang, Ting-Fang

Contact

王廷方 Wang, Ting-Fang

分生所 研究員

  • tfwang@gate.sinica.edu.tw
  • 886-2-2789-9188
  • Lab. 229, IMB

研究領域