The ultimate goal of our research group is to chart and understand how various molecular networks maintain genome stability and human health.
Our research can be categorized into two themes:
- the ultimate goal of deciphering how the genome is non-randomly arranged within the nucleus and understand the impact of this order on diseases such as cancer and premature aging
- we aim to reveal how cells regulate non-coding RNA moelcules in order to maintain genome stability and prevent various neurodegenetive diseases.
Non-random subnuclear DNA organization in genome stability and human health
This first of our two main lab research themes aims to decipher the impact of non-random positioning of DNA loci within the nucleus on fundemental cellular processes as well as various physiological and pathological settings.
What defines preferred DNA locus positions within the nucleus and how this affects genome stability and function is unclear. Gain or loss of chromosomal regions, which can result in genome instability and diseases such as cancer, are commonly instigated by repetitive DNA sequences as these are abundant in eukaryotes and often trigger chromosome restructuring.
Our lab has made a series of findings that are helping us better understand the establishment and function of non-random genome organization within various contexts.
We have discovered how interactions between chromosomal complexes and inner nuclear membrane (INM) proteins organize several chromosomal regions characterized by repetitive DNA sequences at the nuclear envelope in order to maintain silent chromatin, genome stability and cellular lifespan.
We are actively engage in research that will help us understand the role of this spatial organization in various fundemental cellular processes including DNA repair, recombination, and replication.
This work is unlocking many of the secrets of DNA organization in the nucleus.
Understanding the role of this genomic order is also shedding light on the pathobiology of several human diseases such as cancer, muscular dystrophy, premature aging, and cardiac malfunction.
Our research relies primarily on powerful yeast genetic models and also various mammalian cell systems including human stem cells.
Intergenic non-coding RNA in chromosome instability and human disease
The classical view of the flow of genetic information has been from DNA to RNA to proteins. The latter being the ultimate effector proteins.
More recently, so called non-coding RNA molecules that do not lead to proteins have also been found to be able to directly affect the cell by impacting DNA, other RNAs, and proteins.
Such non-coding RNAs can have a positive or negative impact on the cell.
We are actively engaged in characterizing novel and conserved cellular pathways that help cells maximize the positive and limit the negative impact of non-coding RNA molecules.
Characterization of these processes in both yeast and human cells is helping us decipher pathobiological processes underlying a number of neurodegenerative diseases.
This research is also helping us identify completely new avenues for therapeutic intervention for multiple so far incurable brain diseases.
Shokrollahi, M., and Mekhail, K. (2021) Interphase microtubules in nuclear organization and genome maintenance. Trends in Cell Biology.
Patel, P.S., Abraham, K.J., Guturi, K.K.N., Halaby, M-J., Khan, Z., Palomero, L., Ho, B., Duan, S., St-Germain, J., Algouneh, A., Mateo, F., El Ghamrasni, S., Barbour, H., Barnes, D.R., Beesley, J., Sanchez, O., Berman, H.K., Brown, G.W., Affar, E.B., Chenevix-Trench, G., Antoniou, A.C., Arrowsmith, C.H., Raught, B., Pujana, M.A., Mekhail, K., Hakem, A., and Hakem, R. (2021) RNF168 regulates R-loop resolution and genomic stability in BRCA1/2-deficient tumors. Journal of Clinical Investigation 131(3):e140105.
Abraham, K.J., Khosraviani, N., Chan, J.N., Gorthi, A., Samman, A., Zhao, D.Y., Wang, M., Bokros, M., Vidya, E., Ostrowski, L.A., Oshidari, R., Pietrobon, V., Patel, P., Algouneh, A., Singhania, R., Liu, Y., Yerlici, V.T., De Carvalho, D.D., Ohh, M., Dickson, B.C., Hakem, R., Greenblatt, J.F., Lee, S., Bishop, A.J.R., and Mekhail, K**. (2020) Nucleolar RNA polymerase II drives ribosome biogenesis. Nature 585:298-302 doi: 10.1038/s41586-020-2497-0.
Oshidari, R., Huang, R., Medghalchi, M., Tse, E.Y.W., Ashgriz, N., Lee, H.O., Wyatt, H., and Mekhail, K. (2020) DNA repair by Rad52 liquid droplets. Nature Communications 11:695:1-8 doi: 10.1038/s41467-020-14546-z.
Oshidari, R., Mekhail, K., and Seeber, A. (2020) Mobility and repair of damaged DNA: random or directed? Trends in Cell Biology 30:2:144-156
Todd, L.A., Hall, A.C., Pietrobon, V., Chan, J.N., Laflamme, G., and Mekhail, K.** (2020) RNA-cDNA hybrids mediate transposition via different mechanisms. Scientific Reports 10:16034:1-12.
Laflamme, G., and Mekhail, K. (2020) Biomolecular condensates as arbiters of biochemical reactions inside the nucleus. Communications Biology 3:773:1-8
Hall, A., Ostrowski, L.A., and Mekhail, K.** (2019) Phase separation as a melting pot for DNA repeats. Trends in Genetics 35:8:589-600
Ostrowski, L.A., Hall, A.C., Szafranski, K.J., Oshidari, R., Abraham, K.J., Chan, J.N., Krustev, C., Zhang, K., Wang, A., Liu, Y., Guo, R. and Mekhail, K. (2018) Conserved Pbp1/Ataxin-2 regulates retrotransposon activity and connects polyglutamine expansion-driven protein aggregation to lifespan-controlling rDNA repeats. Communications Biology 1:187:1-17 doi: 10.1038/s42003-018-0187-3.
Oshidari, R., Strecker, J., Chung, D.K., Abraham, K.J., Chan, J.N., Damaren, C.J. and Mekhail, K. (2018) Nuclear microtubule filaments mediate non-linear directional motion of chromatin and promote DNA repair. Nature Communications 9:2567:1-11 doi: 10.1038/s41467-018-05009-7.
Chung, K.C., Chan, J.N., Strecker, J., Zhang, W., Ebrahimi-Ardebili, S., Lu, T., Abraham, K.J., Durocher, D. and Mekhail, K. (2015) Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process. Nature Communications 6:7742:1-13 doi: 10.1038/ncomms8742.
Salvi, J.S., Chan, J.N.Y., Szafranski, K, Liu, T.T., Wu, J.D., Olsen, J.B., Khanam, N., Poon, B.P.K., Emili, A., and Mekhail, K. (2014) Roles for Pbp1 and caloric restriction in genome and lifespan maintenance via suppression of RNA-DNA hybrids. Developmental Cell 30(2):177-191. [cover article].
Chan, J.N.Y., Poon, B.P.K., Salvi, J., Olsen, J.B., Emili, A., and Mekhail, K. (2011) Perinuclear cohibin complexes maintain replicative life span via roles at distinct silent chromatin domains. Developmental Cell 20:867-879.
Mekhail, K., and Moazed D. (2010) The nuclear envelope in genome organization, expression, and stability. Nature Reviews Molecular Cell Biology 11:317-328.
Tomson, B. N., Rahal, R., Reiser, V., Monje-Casas, F., Mekhail, K., Moazed, D., and Amon, A. (2009) Regulation of Spo12 Phosphorylation and Its Essential Role in the FEAR Network. Current Biology 19:449-460.
Mekhail, K., Seebacher, J., Gygi, S. P., and Moazed, D. (2008) Role for perinuclear chromosome tethering in maintenance of genome stability. Nature 456:667-670.