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Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.

The understanding of how genetic information may be inherited through generations was established by Gregor Mendel in the 1860s when he developed the fundamental principles of inheritance. The science of genetics, however, began to flourish only during the mid-1940s when DNA was identified as the carrier of genetic information. The world has since then witnessed rapid development of genetic technologies, with the latest being genome-editing tools, which have revolutionized fields from medicine to agriculture. This review walks through the historical timeline of genetics research and deliberates how this discipline might furnish a sustainable future for humanity.

LRRK2 -related Parkinson’s disease ( LRRK2 -PD) is the most frequent form of monogenic PD worldwide, with important therapeutic opportunities, exemplified by the advancement in LRRK2 kinase inhibition studies/trials. However, many LRRK2 variants, especially those found in underrepresented populations, remain classified as variants of uncertain significance (VUS). Leveraging on Malaysian, Singaporean, and mainland Chinese PD datasets ( n  = 4901), we describe 12 Chinese-ancestry patients harboring the LRRK2 p.Arg1067Gln variant, more than doubling the number of previously reported cases (total n  = 23, 87% East Asian, mean age of onset: 53.9 years). We determine that this variant is enriched in East Asian PD patients compared to population controls (OR = 8.0, 95% CI: 3.0–20.9), and provide supportive data for its co-segregation with PD, albeit with incomplete penetrance. Utilizing established experimental workflows, this variant showed increased LRRK2 kinase activity, by ~2-fold compared to wildtype and higher than the p.Gly2019Ser variant. Taken together, p.Arg1067Gln should be reclassified from a VUS to pathogenic for causing LRRK2 -PD.

The frequency and clinical impact of LRRK2 p.G2385R and p.R1628P risk variants in Parkinson’s disease (PD) remain uncertain, particularly across different Asian populations. We genotyped 3058 multi-ethnic Malaysian PD patients, performed detailed phenotyping in 185, and analyzed disease progression in 635 using longitudinal Clinical Impression of Severity Index for PD scores. p.G2385R was largely confined to Chinese (8.2%), while p.R1628P occurred in mixed ancestry (11.0%), Chinese (8.3%), Malays (7.7%), and is reported for the first time in indigenous groups (3.9%). Double-variant carriers had younger onset and more frequently had positive family history. Compared with non-carriers, p.R1628P carriers had lower rates of dementia and orthostatic hypotension, and slower progression of global PD severity. Our findings highlight ethnic differences in the distribution of LRRK2 Asian variants, and suggest that these variants influence onset age, familial occurrence, non-motor features, and disease course, with implications for personalized approaches to PD in Asian populations.

Common and rare variants in LRRK2 influence Parkinson’s disease (PD) risk across diverse populations, and in this study, the rare p.A419V variant was investigated across multiple ancestry cohorts comprising over 200,000 PD cases and controls. In cases of East Asian (EAS) ancestry, p.A419V was significantly associated with increased risk of PD (OR = 2.9; 95% CI: 1.66–5.10; p = 0.0002), and was not in linkage disequilibrium with other LRRK2 coding variants. The variant was significantly associated with a lower age at PD onset in the study cohort, while a meta-analysis of the EAS cases indicated a similar, albeit non-significant trend. LRRK2 protein modelling prediction indicated that binding sites for RAB8A, RAB29 and RAB32 were in close proximity to the p.A419V variant within the ARM domain. Together, these findings confirm the p.A419V as a significant PD risk factor in EAS populations, as well as highlight disease-relevant variants in the ARM domain and the link with LRRK2-RAB signaling.

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.