 |
Partha S.
Sarka, Ph.D.
Assistant
Professor
|
BS, Calcutta University, India
MS, Indian Institute of Technology, Bombay, India
Ph.D., Indian Institute of Science, Bangalore, India
Postdoctoral Training, University of Southern California, Los Angeles
The current research interests in the laboratory focus on three
major areas of molecular genetics.
1. The mechanism by which micro-satellite repeats expand.
The long term goal of our laboratory is to understand the molecular
basis of genome instability. In the past, it has been shown that
the instability of DNA micro-satellite repeat sequences is the
genetic mutation associated with a large number of human genetic
disorders. However, the molecular mechanism by which micro-satellite
repeat sequences become unstable and then expand in human genome
causing complex genetic defects is poorly understood. We are
currently developing novel cell and animal models to understand
the molecular basis of genome instability and repeat expansion.
2. The mechanism by which the expanded repeat sequences cause
complex disease phenotypes.
The instability of micro-satellite repeat sequences is the genetic
mutation associated with several genetic diseases, such as myotonic
dystrophy type 1 and type 2, fragile-X syndrome and several spino-cerebellar
ataxias (SCAs). Myotonic dystrophy type 1 (DM1) is caused by the
expansion of a (CTG)n tri-nucleotide repeat sequence in the 3’ un-translated
region of DMPK located in 19q13.3 whereas type 2 DM (DM2) is caused
by the expansion of (CCTG)n repeat expansion in the first intron
of ZNF9 in chromosome 3. Fragile-X syndrome is caused by the expansion
of a CGG repeat sequence in the 5’ un-translated region of
FMR1 in chromosome X. In all of these disorders the repeat-sequences
are transcribed and the RNA encoding repeat sequence complexes
with muscle-blind proteins. The sequestration of muscle-blind proteins
modulates the splicing pattern of several transcripts. The altered
splicing pattern is believed to cause tissue abnormalities both
in DM1 and DM2.Our long term goal is to understand how the regulatory
switches are disrupted when transcripts encoding repeat sequences
are expressed in DM tissues. We have developed animal models to
understand the RNA toxic gain of function of RNA encoding CUG,
CCUG and CGG repeat sequences.
3. Telomere, cellular senescence and in vivo aging
Telomere, the physical end of each vertebrate chromosome, encodes
a large array of (TTAGGG)n repeated sequences and plays a critical
role in senescence, aging and cancer. DNA polymerase fails to
copy the G-rich strand completely, resulting in depletion of
telomere lengths with every round of mitotic division in all
somatic cells. Progressive shortening of telomeres, after several
rounds of divisions generates critically short telomere at chromosomal
ends. The short telomeres act as a sensor to trigger either senescence
or cell apoptosis in an unknown mechanism. Molecular mechanism
by which short telomeres act as sensors to trigger senescence
and/or apoptosis or in vivo aging is poorly understood. We are
developing several cell and animal models to understand the initiation
of tissue abnormalities that occur with telomere shortening and
aging.
Wakamiya M, Matsuura T, Liu Y, Schuster GC, Gao R, Xu W,
Sarkar PS., Lin X, Ashizawa T. (2006). The role of
ataxin 10 in the pathogenesis of spinocerebellar ataxia type 10,
Neurology, 67, 607-13.
Sarkar PS., Han, J. and Reddy S. (2004) In situ
hybridization analyses of the expression of DMPK gene in various
murine tissue. Neuromuscular Disorders, 14(8-9), 467-506.
Sarkar PS., Paul S., Han J. and Reddy S, (2004) Six5 is required
for spermatogenic cell survival and spermiogenesis Human Molecular
Genetics, 13,(14) 1421-1431.
Sarkar PS., Han, J. and Reddy S. (2004) In situ hybridization
analyses of the expression of DMPK gene in various murine tissue,
Neuromuscular Disorders, 14, 497-31.
Wakimoto H, Maguire CT, Sherwood MC, Vargas MM, Sarkar PS., Han
J, Reddy S, Berul CI, (2002) Characterization of cardiac conduction system
abnormalities in mice with targeted disruption of Six5 gene. J. Interv.Card. Electrophysiol. 7(2) 127-135.
Ito Y, Sarkar PS., Mi Q, Wu N., Bringas P Jr.,
Liu Y, Reddy S, Maxson R, Deng C, Chai Y, (2001) Over-expression of
Smad2 reveals
its concerted action with Smad4 in regulating TGF-β-mediated
epidermal Homeostasis. Developmental Biology, 236(1):
181-194.
Sarkar PS., Appakutan B, Han J, Ito Y, Ai C, Tsai W, Chai, Y,
Stout JT, and Reddy S, (2000) Heterozygous loss of Six5 is
sufficient to cause ocular cataract, Nature Genetics, 25, 110.
Sarkar PS., Chang HC, Boudi FB, and Reddy S,
(1998)CTG repeat show
bimodal amplification in E.coli, Cell, 95, 531.
Gouri-Devi M, Chaudhuri JR, Vasanth A, Saleem M, Gopinath M,
Sarkar PS., and Brahmachari SK,
(1998) Correlation of clinical profile
of myotonic dystrophy with CTG repeat in the myotonin protein kinase
gene, Ind. Journal of Medical Research, 107, 187.
Brahmachari SK, Sarkar PS., Raghavan S, Narayan
M, Maiti A, (1997) Polypurine/polypyrimidine sequences as cis acting transcriptional
regulators,Gene, 190,
17-26.
Brahmachari SK, Gopinath M., Sarkar PS., Balagurumoorthy
P, Tripathi, J, Raghavan S, Shaligram U, Pataskar S, (1996) Simple repetitive
DNA sequences in the genome: structure and functional significance,
Electrophoresis, 16,1705.
Sarkar PS.,and Brahmachari SK, (1992) Intramolecular
triplex potential sequence within a gene down regulates its expression
in vivo, Nucleic
Acids Res., 11;20 (21): 5713-5718.
E-Mail:
pssarkar@utmb.edu
Tel: 409-747-4559 (Office)
409-747-4563 (Lab)
