Introduction
The human genome is constantly threatened by a variety of endogenous and environmental factors. Although most of DNA damage can be repaired through multiple DNA repair pathways, some DNA lesions inevitably escape from the surveillance of DNA repair system and lead to replication forks collapse. Cells evolve a translesion DNA synthesis (TLS) mechanism to incorporate nucleotides opposite damaged lesions by using low fidelity DNA polymerases. TLS includes an error-free pathway and an error-prone pathway, and the latter of which is responsible for the most of genome mutations induced by environmental carcinogens and other DNA damage reagents. Therefore it is believed that reducing error-prone TLS might help control carcinogenesis. Unfortunately, it remains elusive how cells regulate TLS in vivo. The current ongoing projects include: 1, the mechanism of TLS regulation after diversity of DNA damage agents treatment; 2, Genome instability caused by environmental toxic reagents/ chemotherapeutic drugs and related human diseases (infertility, cancer and ageing, etc); 3, the role of RNA binding proteins in DNA repair and genome stability.
Group leader
Dr. GUO Caixia，Professor at Beijing Institute of Genomics, Chinese Academy of Sciences (CAS) and hundred-talent program of CAS. She received her B.S. degree in cell biology from Wuhan University in 1991 and a Ph.D. degree in physiology from the Institute of Zoology, CAS in 1999. She began her first postdoctoral training in the department of Physiology at the University of Kentucky to study the regulation of estrogen receptor beta expression in the ovary. In 2001, she joined Dr. Errol C. Friedberg's lab in UT Southwestern Medical Center as a postdoc to study the mechanisms of DNA damage tolerance. Later she was promoted to be a faculty member in the department of Pathology at UT Southwestern Medical Center (instructor during 2004-2008 and assistant professor since 2008). She is editorial board member for journal Genomics, Proteomics & Bioinformatics since 2010 and has undertaken many research projects from 973, General Program of National Nature Science Foundation of China etc. Her papers have been published in high quality scientific journals, including Cell、Mol Cell、PNAS、EMBO、NAR、Human Mol Genet etc. She has been focusing on studying the mechanisms of translesion DNA synthesis in vivo. The long term goal of her work is to understand how TLS polymerases contribute to genomic instability and tumorigenesis. A wide spectrum of experimental approaches will be employed, including molecular and cellular biology, biochemistry, genomics and proteomics etc.
Recent Progress
Various factors from both endogenous and exogenous sources contribute to DNA damage and genome instability. Translesion DNA synthesis (TLS) is one mode of DNA damaged tolerance pathways which use specialized DNA polymerases to insert and/or extend nucleotides across lesions, thereby limiting stalled replication fork collapse and the potential for cell death. Previous studies have shown that monoubiquitinated PCNA plays an important role in recruitment of Y-family TLS polymerases to stalled replication forks. We firstly have found that MSH2, an important mismatch repair protein associated with hereditary non-polyposis colorectal cancer, can partner with Polκ. Depletion of MSH2 impairs PCNA monoubiquitination and the formation of foci containing Polκ and other TLS polymerases after UV irradiation, suggesting that MSH2 can regulate post-UV focus formation by specialized DNA polymerases in PCNA dependent manner. Also, expression of MSH2 in Rad 18-deficient cells increased UV-induced Polκ and REV1 focus formation without detectable changes in PCNA monoubiquitination, indicating MSH2’s role of regulating post-UV focus formation in PCNA-independent fashions.
The results reveal a novel role of MSH2 in post-UV cellular responses (NAR 2013). On the other hand, we are interested in deciphering the molecular mechanism underlying the accurate bypass of BPDE-dG lesion by Polκ. Benzo[a]pyrene (BP) is one of the common environmental pollutants, which can be metabolized in vivo to form the most tumorigenic and mutagenic BPDE. The formation of BPDE-dG DNA lesion has been closely associated with lung cancer. To date, DNA polymerase κ (Polκ) is the only known DNA polymerase in mammalian cells that can bypass a BPDE-dG lesion efficiently and accurately, thereby reducing mutation risk. However, it is not known how a BPDE-dG lesion is accommodated and how dCTP is selected and incorporated by Polκ. By superimposing the structure of Polκ with Dpo4, a predicted structural gap and the unique N-clasp in Polκ may account for the discrepancy. We have employed various techniques and revealed for the first time that the structure gap determines the polymerase’s processivity and fidelity, and uncovered the key role of the N-clasp in lesion bypass (PNAS 2014). The study has important implications in further our understanding the molecular mechanisms associated with major diseases induced from common environmental pollutants, as well as developing preventive measures and treatments for human diseases.
The normal DNA synthetic and TLS activity by Polκ and predicted structure model of Polκ active site
Selected Publications
1.Tu Y, Liu H, Zhu X, Shen H, Ma X, Wang F, Huang M, Gong J, Li X, Wang Y, Guo C*, Tang TS*. Ataxin-3 promotes genome integrity by stabilizing Chk1. Nucleic Acids Res. (2017). doi: 10.1093/nar/gkx095.
2.Sun X, Cai X, Yang J, Chen J, Guo C*, Cao P*. Overcomes Imatinib Resistance by Depleting BCR-ABL in Chronic Myeloid Leukemia. Mol Cells. (2016). 39(12):869-876. doi: 10.14348/molcells.2016.0023.
3.Liu H, Li X, Ning G, Zhu S, Ma X, Liu X, Liu C, Huang M, Schmitt I, Wüllner U, Niu Y, Guo C*, Wang Q*, Tang TS*. The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53. PLOS Biol. (2016). 14(11):e2000733. doi: 10.1371/journal.pbio.2000733.
4.Zhang H, Zhang C, Yan J, Sun Z, Song S, Sun Y, Guo C*. Transcriptome analysis of the responses to methyl methanesulfonate treatment in mouse pachytene spermatocytes and round spermatids. Gene. (2016). pii: S0378-1119(16)30800-9.
5.Wang QC, Zheng Q, Tan H, Zhang B, Li X, Yang Y, Yu J, Liu Y, Chai H, Wang X, Sun Z, Wang JQ, Zhu S, Wang F, Yang M, Guo C, Wang H, Zheng Q, Li Y, Chen Q, Zhou A, Tang TS. TMCO1 Is an ER Ca(2+) Load-Activated Ca(2+) Channel. Cell. (2016). 165(6):1454-66.
6.Wang K, Ma X, Zhang X, Wu D, Sun C, Sun Y, Lu X, Wu CI, Guo C*, Ruan J*. Using ultra-sensitive next generation sequencing to dissect DNA damage-induced mutagenesis. Sci Rep. (2016). 6:25310.
7.Sun Y, Yang Y, Shen H, Huang M, Wang Z, Liu Y, Zhang H, Tang TS, Guo C*. iTRAQ-based chromatin proteomic screen reveals CHD4-dependent recruitment of MBD2 to sites of DNA damage. Biochem Biophys Res Commun. (2016). 471(1):142-8.
8.Wang Z, Huang M, Ma X, Li H, Tang T, Guo C*. REV1 promotes PCNA monoubiquitination through interacting with ubiquitinated RAD18. J Cell Sci. (2016). 129:1223-1233.
9. Yan J, Zhang H, Liu Y, Zhao F, Zhu S, Xie C, Tang TS, Guo C*. Germline Deletion of Huntingtin Causes Male Infertility and Arrested Spermiogenesis in Mice. J Cell Sci. (2016). (2016). 129: 492-501.
10.Dai K, Qin F, Zhang H, Liu X, Guo C, Zhang M, Gu F, Fu L, Ma Y. Low expression of BMPRIB indicates poor prognosis of breast cancer and is insensitive to taxane-anthracycline chemotherapy. Oncotarget. doi: 10.18632/oncotarget.6613. (2015).
11.Liu Y, Ma X, Guo C*. Effects of the N terminus of mouse DNA polymerase κ on the bypass of a guanine-benzo[a]pyrenyl adduct. J Biochem. pii: mvv118. (2015).
12.Yang Y, Liu Z, Wang F, Temviriyanukul P, Ma X, Tu Y, Lv L, Lin Y, Huang M, Zhang T, Pei H, Chen B, Jansen JG, Wind N, Fischhaber P, Friedberg EC, Tang TS and Guo C*. FANCD2 and REV1 cooperate in the protection of nascent DNA strands in response to replication stress. Nucleic Acids Res. 43, 8325-8339 (2015).
13.Qin Y, Guo T, Li G, Tang TS, Zhao S, Jiao X, Gong J, Gao F, Guo C, Simpson JL, Chen ZJ. CSB-PGBD3 Mutations Cause Premature Ovarian Failure. PLoS Genet. 11(7):e1005419. doi: 10.1371/journal.pgen.1005419 ( 2015).
14.Dong S, Han J, Chen H, Liu T, Huen MS, Yang Y, Guo C, Huang J. The Human SRCAP Chromatin Remodeling Complex Promotes DNA-End Resection. Curr Biol. 24(18):2097-110. (2014).
15.Wang F, Fischhaber PL, Guo C, Tang TS. Epigenetic modifications as novel therapeutic targets for Huntington's disease. Epigenomics. 6(3):287-97. (2014).
16.Li X, Qu F, Xie W, Wang F, Liu H, Song S, Chen T, Zhang Y, Zhu S, Wang Y, Guo C, Tang TS*. Transcriptomic analyses of neurotoxic effects in mouse brain after intermittent neonatal administration of thimerosal. Toxicol Sci. 139(2):452-65 (2014)
17.Gao M, Wei W, Li MM, Wu YS, Ba Z, Jin KX, Li MM, Liao YQ, Adhikari S, Chong Z, Zhang T, Guo C, Tang TS, Zhu BT, Xu XZ, Mailand N, Yang YG, Qi Y, Rendtlew Danielsen JM. Ago2 facilitates Rad51 recruitment and DNA double-strand break repair by homologous recombination. Cell Res. 24(5):532-41. (2014).
18.Liu Y, Yang Y, Tang TS, Zhang H, Wang Z, Friedberg EC, Yang W, Guo C*. Variants of mouse DNA polymerase κ reveal a mechanism of efficient and accurate translesion synthesis past a benzo[a]pyrene dG adduct. Proc Natl Acad Sci USA. 111(5): 1789-1794. (2014).
19.Lv L, Wang F, Ma X, Yang Y, Wang Z, Liu H, Li X, Liu Z, Zhang T, Huang M, Friedberg E, Tang TS, Guo C*. Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation. Nucleic Acid Res. 41(22):10312-10322. (2013).
20.Bétous R, Pillaire MJ, Pierini L, van der Laan S, Recolin B, Ohl-Séguy E, Guo C, Niimi N, Grúz P, Nohmi T, Friedberg E, Cazaux C, Maiorano D, Hoffmann JS. DNA polymerase κ- dependent DNA synthesis at stalled replication forks is important for CHK1 activation. EMBO J. 32(15):2172-2185. (2013).
21.Wang F, Yang Y, Lin X, Wang JQ, Wu YS, Xie W, Wang D, Zhu S, Liao YQ, Sun Q, Yang YG, Luo HR, Guo C*, Han C*, Tang TS*. Genome-wide loss of 5-hmC is a novel epigenetic feature of Huntington's disease. Human Mol Genet 22(18):3641-3653. (2013).
22.Wang J, Chen Q, Wang X, Wang Q, Wang Y, Cheng H, Guo C, Sun Q, Chen Q, Tang TS. Dysregulation of Mitochondrial Calcium Signaling and Superoxide Flashes Cause Mitochondrial Genomic DNA Damage in Huntington’s Disease. J. Biol. Chem. 288(5): 3070-3084. (2013).
23.Zhang X, Lv L, Chen Q, Yuan F, Zhang T, Yang Y, Zhang H, Wang Y, Jia Y, Qian L, Chen B, Zhang Y, Friedberg C, Tang T and Guo C*. Mouse DNA polymerase kappa has a functional role in the repair of DNA strand breaks. DNA Repair. 12(5):377-88. (2013).
24.Wang Z, Wang F, Tang T, Guo C*. The role of PARP1 in the DNA damage response and its application in tumor therapy. Front Med. 6(2):156-164 (2012).
Group Members
Staff:
LIU Yang; ZHANG Hui; YAN Jinting
Doctoral students:
SUN Yazhou; WANG Zhifeng; YANG Yeran; MA Xiaolu; HUANG Min; SUN Zhongshuai
Master students:
XIE Chengmei Xie; ZHANG Xue; LI Huiming; ZHANG Chuanchao
