Anindya Dutta
Byrd Professor and Chair of Biochemistry & Molecular Genetics
M.D., U. of Madras; Ph.D., Rockefeller University
DNA replication and microRNAs in Cancer Cell Proliferation

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Cancer arises from the accumulation of small changes (mutations) in different genes in our normal epithelial cells (for example in the prostate, breast or colon) that eventually result in uncontrolled proliferation of the cells. When normal epithelial cells divide, they require the normal function of many cellular proteins and nucleic acids at certain points in the cell-division process. Cancer cells use these same cellular factors for their proliferation and mis-regulation of these factors help them escape the restraints to proliferation.

Both normal and cancer cells require the actions of many enzymes (DNA replication factors) for copying the DNA in the chromosomes. A cell will stop dividing if it cannot copy its chromosomes or will divide incompletely replicated chromosomes and induce chromosomal damage. One area of research in my laboratory is to identify the factors necessary for DNA replication initiation and determine how they are regulated. We also identify the consequences of mis-regulation of these factors on genomic stability and the cell-cycle. In addition, we use modern tools of genomics to identify sites on human chromosomes that begin the process of DNA replication and how these sites change between different cells.

An independent area of research focuses on small RNAs present in our cells. MicroRNAs and other short RNAs are now known to have profound effects on gene expression and are hypothesized to affect cell proliferation. To study this process in detail we explore the role of microRNAs in inducing quiescence as proliferating myoblasts differentiate into mature muscle fibers. Androgen deprivation is the primary mode of therapy of advanced prostate cancer, and recurrence of the disease is associated with androgen-independence. Thus, we also study how microRNAs and other short RNAs change when androgen-dependent prostate cancer cells are induced to become quiescent by androgen deprivation. Collectively these studies will elucidate how microRNAs and other short RNAs influence cell proliferation.

Selected References

Dey BK, Gagan J, Yan Z, Dutta A. (2012) "miR-26a is required for skeletal muscle differentiation and regeneration in mice." Genes Dev. Oct 26(19):2180-91. doi: 10.1101/gad.198085.112. [PubMed]

Shibata Y, Kumar P, Layer R, Willcox S, Gagan JR, Griffith JD, Dutta A. (2012) "Extrachromosomal microDNAs and chromosomal microdeletions in normal tissues." Science. Apr 336(6077):82-6. doi: 10.1126/science.1213307. Epub 2012 Mar8. [PubMed]

Gagan J, Dey BK, Dutta A. (2012) "MicroRNAs regulate and provide robustness to the myogenic transcriptional network." Curr Opin Pharmacol. 12:383-8. doi: 10.1016/j.coph.2012.02.001. Epub 2012 Mar 2. [PubMed]

Shibata E, Abbas T, Huang X, Wohlschlegel JA, Dutta A. (2011) "Selective ubiquitylation of p21 and Cdt1 by UBCH8 and UBE2G ubiquitin-conjugating enzymes via the CRL4Cdt2 ubiquitin ligase complex." Mol Cell Biol. 31(15):3136-45. doi: 10.1128/MCB.05496-11. Epub 2011 May 31. [PubMed]

Karnani N, Dutta A. (2011) "The effect of the intra-S-phase checkpoint on origins of replication in human cells." Genes Dev. Mar 25:621-33. doi: 10.1101/gad.2029711. [PubMed]

Sun D, Lee YS, Malhotra A, Kim HK, Matecic M, Evans C, Jensen RV, Moskaluk CA,Dutta A. (2011) "miR-99 family of MicroRNAs suppresses the expression of prostate-specific antigen and prostate cancer cell proliferation." Cancer Res. Feb 71:1313-24. doi: 10.1158/0008-5472.CAN-10-1031. Epub2011 Jan 6. [PubMed]

Lin JJ, Milhollen MA, Smith PG, Narayanan U, Dutta A. (2010) "NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells." Cancer Res. Dec 70(24):10310-20. doi: 10.1158/0008-5472.CAN-10-2062. [PubMed]

Dey BK, Gagan J, Dutta A. (2011) "miR-206 and -486 induce myoblast differentiation by downregulating Pax7." Mol Cell Biol. 31:203-14. doi: 10.1128/MCB.01009-10. Epub 2010 Nov 1. [PubMed]

Abbas T, Shibata E, Park J, Jha S, Karnani N, Dutta A. (2010) "CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation." Mol Cell. Oct 40:9-21. doi: 10.1016/j.molcel.2010.09.014. [PubMed]

Shibata Y, Malhotra A, Dutta A. (2010) "Detection of DNA fusion junctions for BCR-ABL translocations by Anchored ChromPET." Genome Med. Sep 2:70. doi: 10.1186/gm191. [PubMed]

Sarkar S, Dey BK, Dutta A. (2010) "MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A." Mol Biol Cell. Jul 21(13):2138-49. doi: 10.1091/mbc.E10-01-0062. Epub 2010May 12. [PubMed]

Karnani N, Taylor CM, Malhotra A, Dutta A. (2010) "Genomic study of replication initiation in human chromosomes reveals the influence of transcription regulation and chromatin structure on origin selection." Mol Biol Cell. Feb 21:393-404. doi: 10.1091/mbc.E09-08-0707. Epub 2009 Dec 2. [PubMed]

Shibata Y, Malhotra A, Bekiranov S, Dutta A. (2009) "Yeast genome analysis identifies chromosomal translocation, gene conversion events and several sites of Ty element insertion." Nucleic Acids Res. 37(19):6454-65. doi: 10.1093/nar/gkp650. Epub 2009Aug 26. [PubMed]

Abbas T, Dutta A. (2009) "p21 in cancer: intricate networks and multiple activities." Nat Rev Cancer. 9:400-14. doi: 10.1038/nrc2657. [PubMed]

Lee YS, Dutta A. (2009) "MicroRNAs in cancer." Annu Rev Pathol. 4:199-227. doi: 10.1146/annurev.pathol.4.110807.092222. [PubMed]

Lew DJ, Burke DJ, Dutta A. (2008) "The immortal strand hypothesis: how could it work?" Cell. Apr 133:21-3. doi: 10.1016/j.cell.2008.03.016. [PubMed]