Uttam SURANA

Regulation of the Cell Division Cycle

Profile

Uttam SURANA
Lab Location: #6-12   Email: mcbucs@imcb.a-star.edu.sg   Tel: 65869503

Uttam Surana undertook his graduate studies at the University of Arizona and obtained a PhD from the Dept. of Molecular and Cellular Biology in 1986. Thereafter, he moved to the Dept. of Engineering at the University of Cambridge where he spent 2 years studying the mechanical properties of bacterial cell surface polymers and their role in cell shape determination. He spent the subsequent four years as a postdoctoral fellow at the Institute of Molecular Pathology in Vienna investigating various aspects of cell division in the budding yeast. He joined the IMCB in 1992. For his outstanding contribution to the understanding of control circuits that regulate cell cycle, Dr Surana was awarded in 2007 Singapore’s National Science Award.

Research

Regulation of the Cell Division Cycle

Cellular activities leading to division are highly regulated both in time and space. Violation of this precision can lead to genomic instability which may result in reduced cellular fitness, unbridled proliferation (cancerous growth) or death of parent and progeny cells. Valuable insights into the way cell division is controlled in complex systems, such as human cells, have come from investigations of relatively simple eukaryotes. The budding yeast Saccharomyces cerevisiae, (the model system we use for our investigations) is one such organism that has served remarkably well due to its amenability to genetic manipulations and because many of the pathways that regulate cell division are highly conserved from yeast to man.

Coordinated execution of cell cycle events is, in-part, imposed by checkpoint controls that ensure that a given event is not initiated until the preceding event is successfully completed. During S phase the genome is monitored by two such major control pathways, namely, DNA replication checkpoint and DNA damage checkpoint. When cells incur replication stress or DNA damage, these pathways prevent initiation of chromosome segregation until the damage is repaired. We have focused our investigations on the mechanisms by which checkpoint pathways prevent execution of mitotic events. Using various genetic and biochemical analysis, we have discovered that the replication checkpoint prevents premature chromosome segregation by directly regulating spindle dynamics, thereby inhibiting precocious spindle elongation. This has led us to closely examine the process of spindle assembly itself. We have uncovered a novel mechanism by which duplicated centrosomes are separated and moved apart to assemble a bipolar spindle. Our findings suggest that cyclin dependent kinase (Cdk1) and polo kinase act synergistically (with Cdk1 serving as a priming kinase for polo kinase) to inactivate the ubiquitin ligase APCCdh1 that mediates the proteolytic destruction of Cin8 and Kip1 kinesins essential for centrosome separation. An extension of these studies has revealed that the regulatory circuit involving Cdk1, Polo kinase, Cdh1 and kinesins is also utilized by the DNA damage checkpoint to prevent segregation of damaged chromosomes. Hence mitotic spindle has emerged as a novel target of S phase checkpoints. To take these studies forward we are investigating the mechanism by which hyper-activation of Rad53 (Chk2) during G2/M leads to mitotic spindle collapse

Recovery from (resumption of cell cycle progression after repair) or adaptation to (escape from arrest in the absence of repair) checkpoint-imposed arrest are also critical aspects of checkpoint regulation and have important implications for chromosome stability. Efforts are now underway to delineate the "adaptation pathway" utilized by cells to escape from DNA-damage-induced arrest

By studying the coordination of various cellular events, we hope to understand the molecular circuits through which eukaryotic cells exercise temporal and spatial control over their activities during cell division. In addition to providing clues to the organizing principles of living cells, such efforts may also lead to the identification of key regulator that could serve as targets for the therapeutic interventions against growth of cancerous cells. We are currently conducting screens to identify anti-proliferative compounds targeting key cell cycle regulators.








Staff

Department: Uttam SURANA

Name: Hong Hwa LIM

Designation: Research Scientist

Email: mcblimhh@imcb.a-star.edu.sg


Name: Vanessa Shi Qin NG

Designation: Research Officer

Email: sqng@imcb.a-star.edu.sg


Name: Gireedhar VENKATACHALAM

Designation: Research Fellow

Email: gireedharv@imcb.a-star.edu.sg


Name: Candice Qiu Xia YAM

Designation: Research Fellow

Email: qxyam@imcb.a-star.edu.sg


Name: Weimei RUAN

Designation: Research Fellow

Email: wmruan@imcb.a-star.edu.sg


Name: David Geok San GOH

Designation: Lab Biologist D

Email: gsgoh@imcb.a-star.edu.sg


Name: Renata PAVLOVIC

Designation: Collaborator

Email: renata_pavlovic@biotrans.a-star.edu.sg


Name: David Boy CHIA

Designation: Collaborator

Email: david_chia@biotrans.a-star.edu.sg


Publications

Kannan S, Venkatachalam G, Lim HH, Surana U, Verma C (2018)
Conformational landscape of Epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket
Chemical Science 9:5212-5222

Lin J, Lee JJH, Paramasivam K, Pathak E, Wang Z, Pramono ZAD, Lim B, Wee KB and Surana U (2017)
Nonsense-mediated decay of glycine decarboxylase transcripts as an anticancer therapeutic strategy for non-small cell lung carcinoma
Molecular Therapy N. A. 9:263-273

Venkatachalam G, Surana U and Clément M-V (2017)
Replication stress-induced endogenous DNA damage drives cellular senescence induced by a sub-lethal oxidative stress
Nuclei Acids Research 45:10564-10582

Radiono S *, Pramono ZAD *, Oh GGK, Surana U, Widiyani S, Danarti R (2017)
Identification of Novel Homozygous SLURP1 Mutation in a Javanese Family with Mal de Meleda
International Journal of Dermatology 56:1161-1168

Her Z, Yong KSM, Paramasivam Kathirvel, Tan WWS, Liu M, Chan XY, Tan SY,  Man HK, Surana U*, and Chen Q* (2017)
An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia
Journal of Hematology and Oncology 10:162-176

Chen C, Lim HH, Shi J, Tamura S, Maeshima K, Surana U and Gan L (2016)
Budding yeast chromatin is dispersed in a crowded nucleoplasm.
Mol Biol Cell 27:3357-3368

Zhang T, Si-Hoe SL, Hudson DF and Surana U (2016)
Condensin recruitment to chromatin is inhibited by checkpoint kinase Chk2 in response to DNA damage
Cell Cycle (In press)

Liang H, Esposito A, De S, Ber S, Collin P, Surana U, Venkitaraman AR (2014)
Homeostatic control of polo-like kinase-1 engenders non-genetic heterogeneity in G2 checkpoint fidelity and timing
Nature Commun 5:4048.

Yu H, Lim HH et al. (2014)
Chaperoning HMGA2 protein protects stalled replication forks in stem and cancer cells
Cell Rep 6:684-697

Khong J.H., Zhang T., Gunaratne J., Blackstock W. and Surana U. (2012)
‘Reductional anaphase’ in replication defective cells is caused by ubiquitin conjugating enzyme Cdc34-mediated deregulation of the spindle
Cell Cycle  11:2896-2910

Surana U., Liang H. and Lim H.H. (2012)
Staging a recovery from mitotic arrest
BioArchitecture 2:33-37. 

Wee K.B., Yio W.K., Surana U., Chiam K.H. (2012)
Transcritpion factor oscillations induce differential gene expressions
Biophysical J 102:2413-2423

Liang H., Lim H.H., Venkitaraman A. and Surana U. (2012)
Cdk1 promotes kinetochore bi-orientation and regulates Cdc20 expression during recovery from spindle checkpoint arrest
EMBO J 31:403-416.

Surana U and Lim H.H. (2011)
Suppressive side of yeast cyclins
Cell Cycle 15;10(18).

Davey G. Wu B., Dong Y., Surana U. and Davey C. (2010)
DNA stretching in the nucleosome facilitates alkylation by an intercalating antitumour Agent
Nucleic Acids Research 38:2081-2088.

Phong M.S., Van-Horn R.D., Li S., Tucker-Kellog G., Surana U. and Ye X.S. (2010)
The p38 MAPK promotes cell survival but is not required for G2 checkpoint arrest of cancer cells in response to DNA damage
Mol. Cell. Biol. 30:3816-3826

Zhang T., Nirantar S., Lim H. H., Sinha I., and Surana U. (2009)
DNA damage checkpoint maintains Cdh1 in active state to inhibit anaphase progression
Developmental Cell , 17:541-551.

Lim H. H., Zhang T. and Surana U (2009)
Regulation of Centrosome Separation in yeast and vertebrates: common threads
Trends in Cell Biology, 19:325-333.

Keng B. N., Surana U, Aguda B. (2009)
Oscillation of the p53-Akt Network: Implication on cell survival and death
PLoS One 4(2):e4407.

Dhar P. K., Thwin C.S., Tun K., Tsumoto Y., Maurer-Stroh, S., Eisenhaber F. and Surana U. (2009)
Synthesizing non-native parts from native genome
J. Biol. Eng. 3(1):2.

Crasta K., Lim H. H., Zhang T., Nirantar S. And Surana U. (2008)
Consorting kinases, end of destruction and birth of a spindle.
Cell Cycle 7:2960-2966.

Crasta K., Lim H. H., T. H. Giddings Jr, M. Winey and Surana U. (2008)
Inactivation of Cdh1 by synergistic action of Cdk1 and Polo kinase is necessary for proper assembly of mitotic spindle
Nature Cell Biology 10: 665-675.

Dong Y., Ng W. K., Surana U., Tan, R. (2008)
Solubilisation and preformulation of poorly water soluble and hydrolysis susceptible N-epoxymethyl-1,8-naphthalimide (ENA) compound
International Journal of Pharmaceutics 356 (1-2):130-136. 

Krishnan V., Dirick L., Lim H. H., Lim T. S. J., Si-Hoe S. L., Cheng C. S., Yap K., Ting A., Schwob E. and Surana U. (2007)
A small molecule inhibitor of cell cycle that irreversibly stalls replication forks and activates S phase checkpoint.
Cell Cycle
6 (issue 13)

Crasta K. and Surana U. (2006)
Disjunction of conjoined twins: Cdk1, Cdh1 and separation of centrosomes.
BMC-Cell Division
(BioMed Central) 1:12.

Crasta K., Huang P., Morgan G., Winey M. and Surana U. (2006).
Activated Cdk1 promotes centrosome separation by preventing Cdh1-mediated proteolysis of microtubule associated proteins.
EMBO J.
25:2551-2563

Zhang Tao, Lim H. H., Cheng C. S. and Surana U. (2006)
Deficiency of centromere-associated protein Slk19 causes premature nuclear migration and loss of centromeric elasticity.
J. Cell Science
119:519-531.

Padmashree C. G. and Surana U. (2005)
Cdc42-mediated Bud Site Assembly in Yeast is Independent of Its GDP/GTP Exchange Factor Cdc24 but Requires COPI Coatamer Complex.
E. J. Cell Biol. 84:939-49.

Krishnan V. and Surana U. (2005)
Taming the spindle for containing the chromosomes.
Cell Cycle
4(3): e68-e71

Tan L. C. A., Padmashree C. G. R. and Surana U. (2005)
Essential tension and constructive destruction: the spindle checkpoint and its regulatory links with mitotic exit.
Biochem J.
386(1):1-13

Krishnan V., Nirantar S., Crasta K., Cheng A. Y. H. and Surana U. (2004)
DNA-Replication Checkpoint prevents precocious chromosome segregation by regulating spindle dynamics
Mol. Cell
16:687-700

Lim H. H., Yeong F. M. and Surana U. (2003)
Inactivation of mitotic kinase triggers translocation of MEN components to mother-daughter neck in yeast
Mol. Biol Cell 14:4734-4743

Lim H. H. and Surana U. (2003)
Tome-1, wee1 and onset of mitosis: coupled destruction for timely entry
Mol. Cell
11:845-846

Chawla, G., Sapra, A., Surana U., and Vijayraghavan U. (2003)
Dependence of Pre-mRNA introns on PRP17, a non-essential slicing factor: implication for efficient progression through cell cycle transition
Nucleic Acid Res.
31:2333-2343

Yeong F. M., Lim H. H. and Surana U. (2002)
MEN, destruction and segregation: Mechanistic link between mitotic exit and Cytokinesis in budding yeast BioEssays 24:659-666.

Yeong F. M., Lim, H. H., Wang, Y. and Surana U. (2001)
Early expressed Clb proteins allow accumulation of mitotic cyclin by inactivating proteolytic machinery during S phase
Mol. Cell. Biol.
, 21:5071-5081.

Padmashree C. G. and Surana U. (2001)
Cdc28-Clb kinase negatively regulates bud-site assembly in the budding yeast
J. Cell Sci
. 114:207-218.

Balasubramanian, M. K., McCollum, D. and Surana, U. (2000)
Tying the Knot: Linking cytokinesis to the nuclear division
J. Cell Sci.
113:1503-1513.

Yeong F. M., Lim H. H., Padmeshree, C. G. and Surana U. (2000)
Exit from mitosis in budding yeast: biphasic inactivation of mitotic kinase and the role of Cdc20.
Mol. Cell
5:501-511.

Goh, P-Y., Lim H. H. and Surana, U. (2000)
Cdc20 proteolysis in G1 requires a destruction box but, unlike Clb2, is not acutely dependent on the activity of Anaphase-Promoting Complex.
Eur. J. Biochem. 267:434-449.

Goh, P-Y. and Surana, U. (1999)
Cdc4, a protein required for the initiation of S phase, plays an essential role during G2/M transition in Saccharomyces cerevisiae.
Mol. Cell. Biol.
19:5512-5522.

Loy, C. J., Lydall, D. and Surana, U. (1999)
NDD1, a high dosage suppressor of cdc28-1N, is required for the expression of a subset of late S phase-specific genes in Saccharomyces cerevisiae.
Mol. Cell. Biol.
19:3312-3327.

Lim, H. H., Goh, P-Y. and Surana, U. (1998)
Cdc20 is essential for the APC-mediated proteolysis of both Pds1 and Clb2 during M phase in budding yeast.
Curr. Biol.
8:231-234.

Dick, T., Surana, U. and Chia, W. (1996).
Molecular and genetic characterization of SLC1, a putative Saccharomyces cerevisiae homolog of the metazoan cytoplasmic dynein light chain 1.
Mol. Gen. Genet.
251:38-43.

Lim, H. H. and Surana, U. (1996).
Cdc20, β-transducin homolog, links RAD9-mediated G2/M checkpoint control to mitosis in Saccharomyces cerevisiae.
Mol. Gen. Genet. 253:138-148.

Christensen, H. E. M., Ramachandran, S., Tan, C-T., Surana, U., Dong, C-H. and Chua, N-H. (1996).
Arabidopsis profilins are functionally similar to yeast profilins: identification of a vascular bundle-specific profilin and a pollen specific profilin.
The Plant Journal. 10(2):269-279.

Lim, H. H., Goh, P-Y. and Surana, U. (1996).
Spindle pole body separation in S. cerevisiae requires dephospho- rylation of Tyr19 residue of Cdc28.
Mol. Cell. Biol.
16:6385-6397.

Lim, H. H., Loy, C. J., Zaman S. and Surana, U. (1996).
Dephosphorylation of Threonine169 of Cdc28 is not required for the exit from mitosis but may be necessary for Start in Saccharomyces cerevisiae.
Mol. Cell. Biol.
16:4573-4583.

Surana, U., Amon, A., Dowzer, C., Mcgrew, J., Byers, B. and Nasmyth, K. (1993).
Destruction of the Cdc28/Clb mitotic kinase is not required for the metaphase to anaphase transition in budding yeast.
EMBO J.
12:1969-1978.

Fitch, I., Dahmann, C., Surana, U., Amon, A., Nasmyth, K., Goetsch, L., Byers, B. and Futcher, B. (1992). Characterisation of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae.
Mol. Biol. Cell
3:805-818.

Amon, A., Surana, U., Muroff, I. and Nasmyth, K. (1992)
Regulation of p34cdc28 tyrosine phosphorylation is not required for the entry into mitosis in S. cerevisiae.
Nature
355:368-371.

Nasmyth, K., Dirick, L., Surana, U., Amon, A. and Cvrckova, F. (1991).
Some facts and thoughts on cell cycle regulation in yeast.
Cold Spring Harbor Symp. Quant.
Biol. 56:9-20.

Moll, T., Tebb, G., Surana, U., Robitsch, H. and Nasmyth K. (1991).
The role of phosphorylation and the CDC28 protein kinase in cell cycle-regulated nuclear import of the S. cerevisiae transcription factor SWI5.
Cell
66:1-20.

Surana, U., Robitsch, H., Price, C., Schuster, T., Fitch I., Futcher, A. B. and Nasmyth, K. (1991)
The role of CDC28 and cyclins during mitosis in the budding yeast Saccharomyces cerevisiae.
Cell
65:145-161.

Thwaites, J. J. and Surana U. (1990)
Mechanical properties of Bacillus subtilis cell wall: effects of removing residual culture medium.
J. Bacteriol. 173:197-203.

Thwaites, J. J., Surana, U. and Jones A. M. (1990).
Mechanical properties of Bacillus subtilis cell wall: Effects of ions and lysozyme
J. Bacteriol. 173:204-210.

Surana, U., Wolfe, A. J. and Mendelson, N. H. (1988)
Regulation of Bacillus subtilis macrofiber twist development by alanine.
J. Bacteriol. 170:2328-2335.

Monod, M., Misaghi, I. G., Mendelson, N. H. and Surana, U. (1986)
Induction of frenching like symptoms in tobacco Macrophomina Phaseolin and its metabolites.
Physiol. Mol. Plant Pathol. 29:19-25.

Mendelson, N. H., Thwaites, J. J., Farve, D., Surana, U., Briehl, M. M., and A. Wolfe. (1985)
Factors contributing to helical shape determination in Bacillus subtilis macrofibers.
Ann. Inst. Pasteur Microbiol. 136A:99-103.