Lilian Kabeche, PhD
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Research Summary
My lab investigates the mechanisms by which cells ensure that they maintain genome stability and how cancer cells with errors in these pathways can be selectively targeted.
Extensive Research Description
The Kabeche lab strives to understand the interplay between chromosomal instability (CIN) and DNA damage response (DDR) defects in cancers and develop new strategies to target CIN in cancer therapy. Chromosomal instability (CIN) is hallmark of cancer whereby cells continuously gain and/or lose whole chromosomes. CIN is present in over 90% of solid tumors and 50% hematopoietic cancers and is correlated with immune evasion, drug resistance, and increased metastasis and poor patient prognosis. CIN itself is self-propagating and can lead to increased genomic instability, whereby chromosome missegregation events can lead to DNA damage during interphase. DNA damage in turn can cause chromosome missegregation creating further genomic instability upon missegregation events. Therefore, it is necessary to understand how the DDR pathway and the mitotic machinery work together and independently to promote genome stability. We have two major areas of research:
Area 1: Investigating the role of the DNA damage repair pathway in mitosis.
A major focus in the lab is investigating how components of the DNA damage response pathway work in mitosis outside of their canonical functions of repairing DNA. We have focused much of our time investigating the role of Ataxia telangiectasia and Rad3 related (ATR) kinase, a master regulator of the DDR pathway. Our previous work demonstrated that ATR is an important component of the centromere and mitotic machinery that ensures faithful chromosome segregation. Our previous work demonstrated that during mitosis, ATR acts independent of its function as part of the DNA damage response pathway and helps promote the activity of a major mitotic kinase: Aurora B. We continue to further study how ATR is activated, regulated and fully elucidate the mechanism by which ATR regulates mitotic processes to ensure that cells segregate their chromosomes faithfully.
In addition to studying ATR, we have also made exciting discoveries on novel functions of other components of the DDR pathway in mitosis.
Area 2: Investigating non-canonical roles of DNA damage repair proteins in interphase.
A second major focus in the lab is investigating how components of the DNA damage response pathway work outside of their function as part of the DNA damage response pathway to promote genome stability. Through our studies we discovered that ATR promotes genome stability by maintaining centromere identity through its regulation of histone chaperones, including DAXX. Loss of ATR, even in the absence of DNA damage led to an inappropriate deposition of H3.3 histones and loss of CENP-A histones at centromeres, leading a loss of centromere identity. This work has opened up many questions of the mechanism by which ATR regulates DAXX and other histone chaperones and how ATR is regulated in the absence of DNA damage. We aim to study this to further understand how healthy and cancer cells are affected by ATR inhibitors, which are currently being tested in the clinic.
Coauthors
Selected Publications
- Molecular mechanism of hyperactivation conferred by a truncation of TRPA1Bali A, Schaefer S, Trier I, Zhang A, Kabeche L, Paulsen C. Molecular mechanism of hyperactivation conferred by a truncation of TRPA1. Nature Communications 2023, 14: 2867. PMID: 37208332, PMCID: PMC10199097, DOI: 10.1038/s41467-023-38542-1.
- ATR protects centromere identity by promoting DAXX association with PML nuclear bodiesTrier I, Black E, Joo Y, Kabeche L. ATR protects centromere identity by promoting DAXX association with PML nuclear bodies. Cell Reports 2023, 42: 112495. PMID: 37163376, DOI: 10.1016/j.celrep.2023.112495.
- Keeping RelApse in Chk: molecular mechanisms of Chk1 inhibitor resistance in lymphomaBlack E, Joo Y, Kabeche L. Keeping RelApse in Chk: molecular mechanisms of Chk1 inhibitor resistance in lymphoma. Biochemical Journal 2022, 479: 2345-2349. PMID: 36416754, PMCID: PMC9704517, DOI: 10.1042/bcj20220461.
- Constant learning - an interview with Lilian Kabeche on setting up an inclusive and welcoming lab.. Constant learning - an interview with Lilian Kabeche on setting up an inclusive and welcoming lab. Commun Biol 2022, 5: 631. PMID: 35768552, DOI: 10.1038/s42003-022-03599-z.
- A mitosis-specific and R loop–driven ATR pathway promotes faithful chromosome segregationKabeche L, Nguyen HD, Buisson R, Zou L. A mitosis-specific and R loop–driven ATR pathway promotes faithful chromosome segregation. Science 2017, 359: 108-114. PMID: 29170278, PMCID: PMC5875943, DOI: 10.1126/science.aan6490.
- Abstract 1410: Proliferation during epithelial-to-mesenchymal transition induces genomic instabilityComaills V, Kabeche L, Morris R, Yu M, Madden M, LiCausi J, Aceto N, Zheng Y, Miyamoto D, Ramaswamy S, Zou L, Haber D, Maheswaran S. Abstract 1410: Proliferation during epithelial-to-mesenchymal transition induces genomic instability. Cancer Research 2017, 77: 1410-1410. DOI: 10.1158/1538-7445.am2017-1410.
- A bifurcated signaling cascade of NIMA-related kinases controls distinct kinesins in anaphaseCullati SN, Kabeche L, Kettenbach AN, Gerber SA. A bifurcated signaling cascade of NIMA-related kinases controls distinct kinesins in anaphase. Journal Of Cell Biology 2017, 216: 2339-2354. PMID: 28630147, PMCID: PMC5551695, DOI: 10.1083/jcb.201512055.
- Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome InstabilitiesBakhoum SF, Kabeche L, Compton DA, Powell SN, Bastians H. Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities. Trends In Cancer 2017, 3: 225-234. PMID: 28718433, PMCID: PMC5518619, DOI: 10.1016/j.trecan.2017.02.001.
- Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal TransitionComaills V, Kabeche L, Morris R, Buisson R, Yu M, Madden MW, LiCausi JA, Boukhali M, Tajima K, Pan S, Aceto N, Sil S, Zheng Y, Sundaresan T, Yae T, Jordan NV, Miyamoto DT, Ting DT, Ramaswamy S, Haas W, Zou L, Haber DA, Maheswaran S. Genomic Instability Is Induced by Persistent Proliferation of Cells Undergoing Epithelial-to-Mesenchymal Transition. Cell Reports 2016, 17: 2632-2647. PMID: 27926867, PMCID: PMC5320932, DOI: 10.1016/j.celrep.2016.11.022.
- Targeting the Process of Mitotic Chromosome Segregation as a Novel Sensitizing Target to Radiation TreatmentLaughney A, Murnane J, Genovese G, Elizalde S, Compton D, Kabeche L, Spratt D, Zaki B, Bakhoum S. Targeting the Process of Mitotic Chromosome Segregation as a Novel Sensitizing Target to Radiation Treatment. International Journal Of Radiation Oncology • Biology • Physics 2015, 93: s50. DOI: 10.1016/j.ijrobp.2015.07.122.
- Shugoshin-1 Balances Aurora B Kinase Activity via PP2A to Promote Chromosome Bi-orientationMeppelink A, Kabeche L, Vromans MJ, Compton DA, Lens SM. Shugoshin-1 Balances Aurora B Kinase Activity via PP2A to Promote Chromosome Bi-orientation. Cell Reports 2015, 11: 508-515. PMID: 25892238, PMCID: PMC4718550, DOI: 10.1016/j.celrep.2015.03.052.
- Numerical chromosomal instability mediates susceptibility to radiation treatmentBakhoum SF, Kabeche L, Wood MD, Laucius CD, Qu D, Laughney AM, Reynolds GE, Louie RJ, Phillips J, Chan DA, Zaki BI, Murnane JP, Petritsch C, Compton DA. Numerical chromosomal instability mediates susceptibility to radiation treatment. Nature Communications 2015, 6: 5990. PMID: 25606712, PMCID: PMC4516720, DOI: 10.1038/ncomms6990.
- Regulation of kinetochore–microtubule attachments through homeostatic control during mitosisGodek KM, Kabeche L, Compton DA. Regulation of kinetochore–microtubule attachments through homeostatic control during mitosis. Nature Reviews Molecular Cell Biology 2014, 16: 57-64. PMID: 25466864, PMCID: PMC4568440, DOI: 10.1038/nrm3916.
- DNA-Damage Response during Mitosis Induces Whole-Chromosome MissegregationBakhoum SF, Kabeche L, Murnane JP, Zaki BI, Compton DA. DNA-Damage Response during Mitosis Induces Whole-Chromosome Missegregation. Cancer Discovery 2014, 4: 1281-1289. PMID: 25107667, PMCID: PMC4221427, DOI: 10.1158/2159-8290.cd-14-0403.
- DNA Damage Response During Mitosis Induces Cancer Chromosomal InstabilityBakhoum S, Zaki B, Compton D, Kabeche L. DNA Damage Response During Mitosis Induces Cancer Chromosomal Instability. International Journal Of Radiation Oncology • Biology • Physics 2014, 90: s780. DOI: 10.1016/j.ijrobp.2014.05.2257.
- A Mitotic Pathway for Radiation-Induced Genome DamageBakhoum S, Kabeche L, Wood M, Suriawinata A, Louie R, Chan D, Petritsch C, Murnane J, Compton D, Zaki B. A Mitotic Pathway for Radiation-Induced Genome Damage. International Journal Of Radiation Oncology • Biology • Physics 2013, 87: s637. DOI: 10.1016/j.ijrobp.2013.06.1684.