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【14th.June】Nucleotide Excision Repair In Vivo:DNA Damage and Repair Maps of the Human Genome

2017-06-13


TOPIC:Nucleotide Excision Repair In Vivo:DNA Damage and Repair Maps of the Human Genome
SPEAKER:胡晋川,研究助理,北卡大学医学院生物化学与生物物理系,美国北卡罗莱纳州,教堂山 27514,
TIME:June 14 (Wednesday)15:00pm 
LOCATION:化学B楼 410会议室
INVITER:仲冬平 教授


报告人简介
   胡晋川,研究助理,北卡大学医学院生物化学与生物物理系,美国北卡罗莱纳州,教堂山 27514, 
教育经历
2004-2012     理学博士,生物化学及分子生物学专业,中国科学院微生物研究所 

研究经历
2012.6-       博士后研究助理(-2017.5.31)/研究助理(2017.6.1-),北卡大学医学院生化及生物物理系,导师:Aziz Sancar教授,美国科学院院士,2015年诺贝尔化学奖得主
研究内容

   主要研究领域是核苷酸切除修复(Nucleotide Excision Repair, NER),它可以修复环境致癌因子如紫外线, 以及化疗药物如顺铂等导致的DNA损伤,与癌症发生和化疗效果密切相关。我首次从细胞内分离了修复过程中切下的含有损伤的DNA片段(JBC 2013),这一发现是NER的切出机制(dual incision mechanism)最直接和确凿的证据,而Sancar教授正是因为发现了NER的分子机制而获得了2015年诺贝尔化学奖。在这个发现的基础上,我建立了XR-seq的方法,通过对NER的切除片段进行高通量测序,第一次做到了在基因组水平上以单碱基分辨率来检测NER(Gene Dev 2015)。利用该方法,我们发现基因组不同区域修复的先后顺序受染色体结构的影响,且与癌症的基因组的突变率相关(Adar, Hu et al. PNAS 2016)。除此之外,我还建立了Damage-seq,使我们第一次能在人类细胞中以单碱基分辨率检测全基因组范围的DNA加成物损伤的位置。用这种技术结合XR-seq,我获得了抗癌药物顺铂造成的DNA损伤与修复的图谱(Hu et al. PNAS 2016)。在此基础上我进一步提高了Damage-seq的灵敏度与特异性(HS-Damage-seq),检测了人类细胞中UV损伤在形成和修复过程中的分布,发现了转录因子结合对DNA损伤形成的影响(PNAS 2017,已接收)。这两种方法使我们第一次可以从基因组水平研究DNA损伤与修复,为从基因组水平上研究转录,染色体结构等因素对DNA损伤,修复及其引起的突变的影响,以及进一步对癌症发生与化疗效果等的影响提供了技术基础。


2004.9-2012.4 博士研究生,中国科学院微生物研究所,导师:黄力研究员
博士期间我主要研究嗜高温古菌硫磺矿硫化叶菌的DNA引发酶,发现该酶除了参与DNA复制,还可能参与了DNA双链断裂损伤修复的非同源末端连接途径。


发表论文
1. Hu J*, Adebali O*, Adar S, and Sancar A. Dynamic maps of UV damage formation and repair for the human genome. Proc Natl Acad Sci U S A. 2017, In Press.
2. Hu J, Lieb JD, Sancar A, and Adar S. Cisplatin DNA damage and repair maps of the human genome at single-nucleotide resolution. Proc Natl Acad Sci U S A. 2016, 113(41):11507-11512 (Research Highlight In This Issue)
3. Adar S*, Hu J*, Lieb JD, and Sancar A. Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis. Proc Natl Acad Sci U S A. 2016, 113(15): E2124-E2133
4. Hu J*, Adar S*, Selby CP, Lieb JD, and Sancar A. Genome-wide analysis of human global and transcription-coupled excision repair of UV damage at single-nucleotide resolution. Genes & Development. 2015, 29(9): 948-960. (Research Highlight In This Issue)
5. Hu J, Choi JH, Gaddameedhi S, Kemp MG, Reardon JT, Sancar A. Nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying DNA damage in vivo. J Biol Chem. 2013, 288(29): 20918–20926. 
6. Hu J, Guo L, Wu K, Liu B, Lang S, Huang L. Template-dependent polymerization across discontinuous templates by the heterodimeric primase from the hyperthermophilic archaeon Sulfolobus solfataricus. Nucleic Acids Res. 2012, 40(8): 3470-3483
7. Hu J, Adar S. The Cartography of UV-induced DNA Damage Formation and DNA Repair. Photochem Photobiol. 2017, 93 (1): 199-206 Review.
8. Li W, Hu J, Adebali O, Adar S, Yang, Y, Chiou, YY, and Sancar A. General method for genome-wide mapping of nucleotide excision repair: application to UV and benzo[a]pyrene-induced DNA damage. Proc Natl Acad Sci U S A. 2017, In Press.
9. Adebali O, Chiou YY, Hu J, Sancar A, Selby CP. Genome-wide Transcription-coupled Repair in E. coli is Mediated by Mfd Protein. Proc Natl Acad Sci U S A. 2017, 114(11): E2116–E2125.
10. Kemp MG and Hu J. Post-excision Events in Human Nucleotide Excision Repair. Photochem Photobiol. 2017, 93 (1): 178-191 Review.
11. Canturk F, Karaman M, Selby CP, Kemp MG, Kulaksiz-Erkmen G, Hu J, Li W, Lindsey-Boltz LA, and Sancar A. Nucleotide excision repair by dual incisions in plants. Proc Natl Acad Sci U S A. 2016, 113(17):4706-10
12. Lindsey-Boltz LA, Kemp MG, Hu J, Sancar A. Analysis of ribonucleotide removal from DNA by human nucleotide excision repair. J Biol Chem. 2015, 290(50): 29801-7.
13. Sancar A, Lindsey-Boltz LA, Gaddameedhi S, Selby CP, Ye R, Chiou YY, Kemp MG, Hu J, Lee JH, and Ozturk N. Circadian Clock, Cancer, and Chemotherapy. Biochemistry, 2015, 54(2): pp 110–123. Review
14. Kemp MG, Gaddameedhi S, Choi JH, Hu J and Sancr A. DNA Repair Synthesis and Ligation Affect the Processing of Excised Oligonucleotides Generated by Human Nucleotide Excision Repair. J Biol Chem. 2014, 289(38): 26574-26583. 
15. Choi JH, Gaddameedhi S, Kim SY, Hu J, Kemp MG, Sancar A. Highly specific and sensitive method for measuring nucleotide excision repair kinetics of ultraviolet photoproducts in human cells. Nucleic Acids Res. 2014, 42(4): e29.
16. Liu Y, Guo L, Guo R, Wong RL, Hernandez H, Hu J, Chu Y, Amster IJ, Whitman WB, Huang L. The Sac10b homolog in Methanococcus maripaludis binds DNA at specific sites. J. Bacteriol. 2009, 191(7): 2315-29.
17. Wu K, Lai X, Guo X, Hu J, Xiang X, Huang L, Interplay between primase and replication factor C in the hyperthermophilic archaeon Sulfolobus solfataricus. Mol Microbiol. 2007, 63(3):826-37.


参与会议
1. 2016,美国国立癌症研究所染色体生物学研讨会,展板,美国,马里兰州,贝塞斯达
2. 2016,高登DNA损伤,突变与癌症研究会议,展板,美国,加州,文图拉
3. 2016,高登DNA损伤,突变与癌症研讨会,展板与报告,美国,加州,文图拉
4. 2015,发育,衰老,疾病与表观遗传学研讨会,展板,美国,北卡州,教堂山
5. 2015,美国国立癌症研究所染色体生物学研讨会, 展板,美国,马里兰州,贝塞斯达
6. 2013,美国国立卫生研究院DNA修复视频会议年轻研究者报告(每年仅选出三个年轻研究者,报告视频链接:http://videocast.nih.gov/Summary.asp?File=18017&bhcp=1)
7. 2011,中国-丹麦古菌生物学及生物技术研讨会,展板,中国,武汉
奖励与荣誉
• 2015,北卡大学Joseph S. Pagano杰出论文奖
• 2015,北卡大学博士后杰出研究奖(每年全校所有专业获奖者总计10人)
• 2012,北京市高校优秀毕业生
• 2012,中国科学院研究生院优秀毕业生
• 2012,中国科学院院长奖学金优秀奖
• 2012,中国科学院微生物所所长奖学金
• 2009,中国科学院研究生院优秀学生


报告摘要

Nucleotide Excision Repair In Vivo:
DNA Damage and Repair Maps of the Human Genome
Abstract
DNA bulky adducts such as UV-induced damage can interfere with DNA replication and transcription, lead to mutation and cell death, and finally cause cancer and other disease. Nucleotide excision repair is the sole mechanism to repair these damage in humans. In nucleotide excision repair the damaged base(s) are removed by concerted dual incision bracketing the lesion to generate oligonucleotides of 26-27 nt in human cells. Though this reaction was reconstituted and well-studied in vitro, whether it has the same mechanism in vivo and how it is affected by chromosomal factors were unclear. 


To answer these questions, I isolated the in vivo excised oligonucleotides for the first time and demonstrated the congruence of in vivo and in vitro data on nucleotide excision repair. Then I developed methods for detecting the site of DNA bulky adducts formation (Damage-seq) and repair (XR-seq) at single nucleotide resolution and have generated damage and repair maps for the entire human genome. In Damage-seq, the exact locations of DNA damage are determined by the arrested DNA polymerase at damage sites. In XR-seq, the excised oligonucleotides containing DNA damage are captured by TFIIH-IP and subjected to high-throughput sequencing. DNA damage and repair maps generated by these methods indicated that while damage formation is mainly determined by sequence context and essentially uniform throughout the genome, repair is affected by chromatin states, transcription and other factors. The combination of damage and repair maps provides a holistic perspective of bulky adduct formation and repair of the human genome and has potential applications in cancer prevention and chemotherapy.




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