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Title: The role of lemur tyrosine kinase 3 (LMTK3) in DNA damage repair
Author: Lit, Lei Cheng
ISNI:       0000 0004 7657 3606
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The lemur tyrosine kinase 3 (LMTK3) is a member of the receptor tyrosine kinase family, previously identified as an oestrogen receptor alpha regulator that involve in endocrine resistance. Importantly, LMTK3 expression has been found in colorectal cancer, non-small cell lung cancer and particularly elevated in high-grade breast cancer. Indeed, LMTK3 overexpression promotes cancer progression and regulates gene transcription of LMTK3-bound tumour suppressor-like genes. Nonetheless, the function and the molecular mechanism of this kinase to overcome drug cytotoxicity in chemotherapy, remain poorly defined. The aims of this thesis are to discover whether LMTK3 plays a role in DNA damage response to doxorubicin and elucidate its mechanism of actions. To study LMTK3 function, we generated stably overexpressed-LMTK3 cell lines. Next, we found that in doxorubicin treatment, these cell lines were more resistant as compared with its control cells. In response to doxorubicin, at the early response, the overexpression of LMTK3 reduced phosphorylation of ATM at serine 1981, which led to decrease serine 428 KAP1 and serine 139 H2AX phosphorylation. In addition, overexpressed-LMTK3 cells reduced H2AX monoubiquitination. These series of events attenuate doxorubicin-induced DNA damage, protecting cells from death. Then we demonstrated that LMTK3 facilitates homologous recombination repair rather than non-homologous end-joining repair. We determined that LMTK3 directly binds to RAD51 and maintains the RAD51 protein level. Overexpression of LMTK3 maintained RAD51 in the nuclear compartment and may recruit RAD51 to filaments which enhance the repair of damaged DNA. Our present study provides a mechanistic insight of LMTK3 role in protecting cells from doxorubicin-induced DNA damage and promoting homologous recombination repair pathway through RAD51 binding.
Supervisor: Stebbing, Justin ; Giamas, Georgios ; Cheah, Swee Hung ; Roslani, April Camilla Sponsor: Universiti Malaya ; Kementerian Pengajian Tinggi, Malaysia
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral